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For peer review only

Mind The Gap: Discrepant costs between actual and recommended treatments of infant functional

gastrointestinal disorders

Journal: BMJ Open

Manuscript ID bmjopen-2016-015594

Article Type: Research

Date Submitted by the Author: 15-Dec-2016

Complete List of Authors: Mahon, James Lifschitz, Carlos; Hospital Italiano de Buenos Aires, Departamento de Pediatria

Ludwig, Thomas Thapar, Nikhil Glanville, Julie; University of York, York Health Economics Consortium Miqdady, Mohamad; Ped. GI, Hepatology & Nutrition Division Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates, Pediatrics Saps, Miguel; Nationwide Children’s Hospital, Columbus, Ohio, USA Seng Hock , Quak ; National University of Singapore, Singapore Lenoir-Wijnkoop, Irene; University of Utrecht, Utrecht, The Netherlands Edwards, Mary; University of York, York Health Economics Consortium Wood, Hannah SZAJEWSKA, Hania; The Medical University of Warsaw, Dept of Paediatrics

<b>Primary Subject

Heading</b>: Paediatrics

Secondary Subject Heading: Gastroenterology and hepatology

Keywords: Functional bowel disorders < GASTROENTEROLOGY, Community child health < PAEDIATRICS, Health economics < HEALTH SERVICES ADMINISTRATION & MANAGEMENT

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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Mind The Gap: Discrepant costs between actual and recommended treatments of infant functional

gastrointestinal disorders

Authors: James MAHON1*, Carlos LIFSCHITZ2*, Thomas LUDWIG3, Nikhil THAPAR4,

Julie GLANVILLE1, Mohamad MIQDADY5, Miguel SAPS6, Seng Hock QUAK7, Irene

LENOIR-WIJNKOOP8, Mary EDWARDS1, Hannah WOOD1, Hania SZAJEWSKA9

*contributed equally

1 York Health Economics Consortium, University of York, York, UK

2 Hospital Italiano, Buenos Aires, Argentina

3 Nutricia Research, Singapore

4 Great Ormond Street Hospital, London, United Kingdom

5 Pediatric Gastroentrology, Hepatology & Nutrition Division Sheikh Khalifa Medical

City, Abu Dhabi, United Arab Emirates

6 Nationwide Children’s Hospital, Columbus, Ohio, USA

7 National University of Singapore, Singapore

8 University of Utrecht, Utrecht, The Netherlands

9 Medical University of Warsaw, Warsaw, Poland

Word count: 4,122

Figures: 1

Tables: 3

Corresponding author: Professor Hania Szajewska

Department of Paediatrics, Medical University of Warsaw,

Warsaw, Poland

[email protected]

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ABSTRACT

Objectives: To estimate the cost of functional gastrointestinal disorders (FGIDs) and

related signs and symptoms in infants to the third party payer and to parents.

Study design: A systematic review was undertaken to identify any existing cost of

illness studies on FGIDs in infants and to also identify treatments that are and have

been used for FGIDs in infants to feed into a de novo cost calculation for England

which also incorporated analysis of existing data sources. Where necessary, for the

calculation estimates and assumptions were always chosen to provide a lower bound

of the potential cost.

Results: In total, 12364 records were identified from database searching and 78

from additional searches of which 34 studies were included that contributed data

about treatments of FGIDs and related signs and symptoms in infants: 3 articles

provided partial information on the cost of FGIDs in infants with the remaining papers

providing evidence on different treatments used in infants with suspected FGIDs. The

de novo calculation estimated that the total costs of treating FGIDs in infants in

England were at least £72.3 million per year in 2014/15 of which £50.0 million was

National Health Service expenditure on prescriptions, community care, and hospital

treatment. Parents incurred £23.2 million in costs through purchase of over the

counter remedies.

Conclusions: The total cost presented here is likely to be a significant

underestimate as only lower bound estimates were used where applicable, and e.g.

costs of alternative therapies, inpatient treatments or diagnostic tests, and time off

work by parents could not be adequately estimated and were omitted from the

calculation. The number and kind of prescribed products and products sold over the

counter to treat FGIDs suggest that there are gaps between treatment guidelines,

which emphasize parental reassurance and nutritional advice, and their

implementation.

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Strengths and limitations of the study

Strengths

• This is a systematic review with a registered protocol, following rigorous

methods, including an extensive search, and data extraction and study quality

assessment by two independent reviewers.

• The review and de novo calculation are focused on more recent studies and

data to ensure currency and most recent practice are reflected in terms of

care of FGIDs and related signs and symptoms.

• Where necessary, for the de novo calculation estimates and assumptions

were always chosen to provide consistently a lower bound of the potential

cost.

Limitations

• The searches were limited to studies published since 2005 in English.

• The total cost presented here this is likely to be a significant underestimate of

the true cost as lower bound estimates were used where applicable, and

several costs could not be adequately estimated and were omitted from the

calculation.

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Contributions: All authors gave input on the design and aim of the systematic

review. HW, JMG and TL designed the search strategy; CL, HS, IL-W, MM, MS, and

SHQ gave input to the search strategy and the inclusion and exclusion criteria; JMG

and JM defined the data extraction elements; JM, JMG, ME, and TL wrote the

protocol, CL, JM, JMG, ME, and TL wrote this manuscript; CL, HS, IL-W, MM, MS,

NT, and SHQ revised the protocol and this manuscript.

Funding: This work was carried out by York Health Economics Consortium, an

independent consultancy, and was funded by Nutricia Research, Utrecht, The

Netherlands. The systematic review protocol was developed by Julie Glanville and

James Mahon.

Competing interests: TL is an employee of Nutricia Research. IL-W is an employee

of Danone SA. HW, JM, JMG, and ME are employees of YHEC. HS reports no

conflicts of interest for this piece of work. CL, HS, MM, NT, and SHQ have served as

consultants, advisory board members and/or speakers for companies manufacturing

infant formulas, foods and probiotics or prebiotics. MS has served as a consultant for

a medical food company.

Data sharing: no additional data available.

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ABBREVIATIONS

A&E Accident & Emergency department (UK)

COI Cost of illness

FGID Functional Gastrointestinal Disorder

GI Gastrointestinal

GP General Practitioner

HCP Healthcare professional

HES Hospital Episode Statistics

HSCIC Health and Social Care Information Centre

NHS National Health Service (UK)

OTC Over the counter

PPI Proton pump inhibitor

PRISMA Preferred Reporting Items for Systematic review and Meta-Analysis

UK United Kingdom

USA United States of America

YHEC York Health Economics Consortium

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INTRODUCTION

Functional gastrointestinal disorders (FGIDs), according to Rome IV criteria, are

defined as variable combinations of chronic or recurrent gastrointestinal (GI) signs

and symptoms without obvious structural or biochemical alterations 2. Within the first

year after birth, such symptoms can be observed in up to 50% of infants 3 4.

A recent meta-review reported that the worldwide prevalence of the three most

common FGIDs in infants, infantile regurgitation, colic, and functional constipation, is

approximately 30%, 20%, and 15%, respectively 4. In addition, many children may

present with a combination of FGIDs and related signs and symptoms 3 4. Although

considered mostly as benign conditions, FGIDs are a source of concern and

frustration for families that may cause them to seek the advice from health care

professionals (HCPs) 3 4.

Diagnostic criteria for FGIDs have been defined and are being continuously revised,

and algorithms have been developed for their practical management by HCPs .

These algorithms build on parental support, reassurance, and nutritional advice as

first line therapy. Depending on the specific condition, advice is given on issues

including feeding frequency and volume as well as allergen avoidance in both breast

and formula fed infants. Despite stringent diagnostic criteria and treatment

recommendations, daily practices may broadly deviate from these and infants

suffering from FGIDs and related signs and symptoms receive a large number of

other treatments that are either contraindicated or not substantiated scientifically 8.

The aim of this study was to estimate the cost of functional gastrointestinal disorders

(FGIDs) and related signs and symptoms in infants to the third party payer and to

parents.

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METHODS

The study employed a two stage methodology to estimate the cost of illness (COI of

infant FGIDs.

Stage One

A systematic review was undertaken to identify any studies published in or after 2005

that provided information on a) the frequency and volume of reported treatments of

FGIDs and related signs and symptoms (regardless of their effectiveness; b) costs to

third party payers and/or parents of infants with FGIDs and related signs and

symptoms of prescribed treatments, over the counter (OTC) or home remedies, visits

to health care professionals and other providers of complementary and other forms

of care, and changes in infant formula; c) loss of income for parents/carers of infants

with FGIDs and related signs and symptoms, or the specific symptom combinations

described above, through inability to return to work, time taken off work, and out of

pocket costs.

Studies of infants less than twelve months old with colic, regurgitation and/or

functional constipation were eligible for inclusion if the underlying cause of illness

was believed to be related to a FGID. Studies in preterm infants were excluded. The

details of the review methods and protocol have been published elsewhere . Studies

reporting data about treatments, signs and symptoms of FGIDs were considered

separately to studies reporting direct and indirect costs.

Stage Two – De novo COI calculation for one country

Following the systematic review protocol, if no existing COI calculation was available

for any country, then a de novo calculation for one country was to be undertaken

using evidence from the literature review (where appropriate), and from readily

available data sources. England was chosen as an exemplar country due to the

availability and quality of data on healthcare resource use, both publicly and

privately, and the availability of these data in the English language.

Potential costs were considered for the third party payer (the National Health Service

(NHS) in England) and for parents/carers. In constructing the calculation, estimates

and assumptions (where necessary) were chosen to provide a lower bound

(minimum) of the potential overall cost. In doing so, the interpretation of the

calculation is that the true COI can be no lower than that estimated.

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Publicly funded healthcare resource use

Prescription data

Potential medicinal remedies for infant FGIDs and special infant formulas were

identified either through the systematic review or via clinical expert opinion. The

prescribed items considered in the analysis with the number and costs of

prescriptions made in England are available from the Health and Social Care

Information Centre (HSCIC). Data were available for 2014/15 and cover prescriptions

made in both primary and secondary care.

Although the prescription analysis is precise on the cost of medications and formula,

the analysis is not clear in all cases about whether the medicine or formula was

indicated specifically for infants with FGIDs or specifically for those aged under 12

months. Therefore, we made some assumptions. We assumed the colic remedies

would be for children under 12 months of age. If colicky symptoms had not cleared

by this time, further investigations would be undertaken and it is difficult to envisage

situations where a persistently crying baby who appeared in pain would still be

prescribed medications that must have proven ineffective up to that point. In addition,

the Rome III criteria for infantile colic include only children that are younger than four

months, although it is not certain that this, in itself, would stop a general practitioner

(GP) prescribing colic remedies once an infant reached that age.

For gastroesophageal reflux, the combination of aluminium hydroxide and

magnesium carbonate (Gaviscon infant®) is suitable up to 24 months of age.

However, clinical advice and evidence from systematic reviews suggests that nearly

all reflux and regurgitation would clear by the age of 12 months. Hence, we

estimated that 90% of the Gaviscon infant® would be prescribed to children under 12

months.

Proton pump inhibitors (PPIs) have not been included in the analysis as these should

only be used in diagnosed gastroesophageal reflux disease which is not a FGID.

However, proton pump inhibitors have been reported to be over-prescribed by

pediatricians in general, and more specifically for infantile colic, though these have

been proven to be ineffective and have frequent side effects. 11-13

For constipation, docusate sodium (Ducosol paediatric®) is suitable for those up to

the age of 12 years. Hence, we have divided the number of prescriptions and the

cost by 12 to provide an estimate of prescriptions to those under 12 months. Infant

glycerol suppositories were also included, and we assumed that all prescriptions

were for infants below 12 months, because a paediatric formulation is available for

those over 12 months. We considered prescriptions of lactulose, but it was not

possible to isolate a preparation just for infants and children. Most preparations for

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the treatment of constipation are not recommended for those under 12 months of age

even if, in practice, they may be used with infants.

Primary and community care costs

From a community care perspective, an assumption was made that infants with

infantile colic will require one extra home visit from a health visitor compared to

babies without colic. Evidence suggests that the incidence of infantile colic is

between 10% and 40%. A National Institute of Health Research funded ongoing trial

of supporting parents of infants with colic indicates an incidence of 1 in 5 infants.

Applying the 1 in 5 figure to the 697,852 infants born live in England and Wales in

2015 means that approximately 140,000 infants in England experienced colic in that

year.

Without data on the number of GP appointments, it has been assumed that as

prescriptions will in most cases have been written by a GP, the number of

appointments must, as a minimum, be equal to the number of prescriptions written.

Although it is possible that more than one item could have been written at the same

time, it was considered that in routine clinical practice for infantile colic only one

medicine would have been tried at any one time. Follow up consultations have not

been included in the analysis nor have any consultations that resulted in no

prescription. As such, the estimate that GP consultations will be equal to the number

of prescriptions will result in a conservative estimate of the true impact of GP time

spent dealing with FGIDs.

Hospital care

Data on hospital care and activity are collected in England by each hospital and

collated each year as the Hospital Episode Statistics (HES) dataset, available

through the Health and Social Care Information Centre (HSCIC). This dataset

contains information on all accident and emergency (A&E) and outpatient

attendances and admitted patient care in England.

The admitted patient care dataset provides information on all planned and unplanned

hospital admissions, including those seen as day cases. Planned admissions are

usually for surgical procedures. Unplanned admissions can be for emergency

operations but can also be for patients staying in hospital for observation. Data are

available on the primary ICD10 diagnostic code of the admitted patient as well as the

age of the patient. We received expert advice on the ICD10 codes that would be

used exclusively for infant FGIDs. We excluded codes that could also be used for

other conditions, resulting in our estimate being a lower bound of actual admissions

for FGIDs.

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HES collates data on all patients who present at hospital emergency rooms (A&E in

the UK). Data are not as detailed as those for admitted patient care, although age is

recorded and along with a broad diagnosis group, but no ICD10 code. Data by age

and diagnosis jointly are not readily available.

Data are available from HES on outpatient appointments. Outpatient appointments in

the UK usually relate to appointments with hospital-based consultants or diagnostic

professionals, or in some cases to receive a simple treatment that does not require a

hospital bed. Outpatient appointments are, in almost all cases, made through GP

referral. A patient in England cannot in most cases access specialist treatment or

diagnostic procedures without a GP referral unless they pay privately. Outpatient

data are available by ICD10 code, but not routinely broken down by age.

Over the counter colic remedies and special infant formulas

Data were provided by IRi (Information Resources, INC) on OTC sales of colic

remedies, simethicone, lactase, various gripe waters, and special infant formulas for

the period 2014/15.

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RESULTS

Stage One – Systematic review

The details of the protocol of the systematic review have been published elsewhere 9.

In total, 12364 records were identified from database searching and 78 from

additional resources. After the steps of duplicate removal, title, abstract, and full text

screen, 31 studies were identified that provided data about treatments, signs and

symptoms of FGID in infants: 26 were randomized controlled trials and five were

case series . Almost half (15) of these studies were undertaken in Europe (including

three in the UK). Four studies were conducted in the USA, three in Australia, three in

Turkey, and one each in Brazil, Israel, Canada, Iran, and Nigeria. Twenty nine

studies included infants with colic and two studies included infants with constipation.

Several different interventions were addressed in the eligible studies. Ten studies 24

25 31 34-40 investigated the impact of probiotic supplementation; four particular types of

formula 22 41-43; three used multiple types of interventions (alone or in combination) 26

27 33; three acupuncture 44-46; three chiropractic treatment 16-18; two changed the

maternal diet 23 32; two used natural remedies 21 29; one glucose 28; one parental

counselling 19 and one a homeopathic remedy 30. The PRISMA diagram for the

record selection process is shown in figure 1.

A further three studies, all from the USA, reported an aspect of the cost of illness of

FGID. Two studies analysed the costs of A&E and inpatient stays for constipation.

Although these studies did not provide a cost for children aged below 12 months,

they allow us to estimate such costs by isolating the numbers of attendances in

infants under 12 months of age and then applying the mean cost per patient from the

studies. We assumed that the mean cost is the same regardless of age.

The third study looked at the average cost of inpatient care for patients aged 0-18

years in the USA with a variety of FGIDs. This was not the patient population of

interest and the cost for children under 12 months of age could only be inferred by

applying a simple weighting of the population overall of children under 12 months as

a proportion of the population under 18 years of age. The three identified COI studies

were therefore of limited use in addressing the research question.

Information on treatments from the studies was extracted and a full list of the

prescribed items considered

No information was identified in the review on parental or caregiver costs.

Stage Two – De novo COI calculation for England

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Prescription data

Medicines or formulas prescribed in England to infants are fully covered by the NHS.

A full list of the prescribed items considered, the number of prescriptions and the

associated cost is shown in Table 1.

We estimated the total number of prescriptions of colic and FGID medications for

infants below 12 months in 2014/15 to be 521,000, at a cost of £5.8 million and the

total number of prescriptions of colic and anti-reflux formulas to be 58,000 at a cost

of £0.9 million.

Table 1: Prescription analysis 2014/15

Type of solution Sum of Items (thousands)

Cost £ (millions)

Medicinal 521.2 5.8

Colic 115.1 1.1

Colief_Infant Dps 64.7 0.9

Dentinox_Infant Colic Dps 3.1 <0.1

Infacol_Susp 40mg/ml S/F 47.1 0.2

Nurse Harveys_Gripe Mix <0.1 <0.1

Woodward's_Gripe Water 0.2 <0.1

Constipation 24.8 <0.1

Glycerol Suppository Infants (1g) 23.9 <0.1

Docusol_Paed Soln 12.5mg/5ml S/F (1/12 of total prescriptions)

0.9 <0.1

Reflux & Regurgitation 381.4 4.7

Gaviscon Infant_Sach 2g (Dual Pack) S/F (9/10 of total prescriptions)

381.4 4.7

Colic and regurgitation formulas 58.8 0.9


Colic 3.0 0.1 Grand Total 580.0 6.7


We estimated that the average time for a home visit, including travel, would be 30

minutes, with a unit cost per half hour of £25 giving a cost of £3.5 million.

Data from Table 1 for colic and FGID medicines and formulas suggested a total of

578,000 prescriptions. At a cost of £45 per 11.7 minute appointment this would

equate to a cost to the NHS of £26.0 million. For the allergy and other special infant

formulas the cost of GP time would be £30.9 million.

Hospital care - Admitted Patient Care

The total number of admissions for each of the ICD10 diagnosis codes for FGIDs or

colic, with the length of stay included in the analysis, are shown in Table 2.

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16,183 infants were admitted to acute hospitals in 2014/15 in England due to FGIDs

amounting to 25,800 bed days. The cost to the NHS of a day in a hospital bed in

2014/15 was £359.13. The total cost of the admitted patient care was therefore £9.3

million. This cost is only for bed days and does not include the cost of any diagnostic

procedures.

Hospital Care – Accident & Emergency Visits

The number of A&E attendances for children under 12 months of age was 483,000 in

2014/15 and the percentage of all attendances for all ages for all gastrointestinal

conditions was 5.7%. We estimated the number of attendances due to GI conditions

in infants aged under one year by assuming that the proportion of attendances due to

GI conditions is the same across age groups. Evidence from the USA identified in the

literature review suggested that 9.4% of all Emergency Department visits in the USA

due to constipation were in those aged under 12 months. If a similar pattern is seen

in England, and for all FGIDs, then this means that the estimated attendances we

have calculated are likely to be a significant underestimate.

Table 2: Number of admissions and mean length of stay for patients with

FGID or colic in England 2014/15

ICD10

code

Description Number of

admissions

Mean length of

stay

k21.9 Reflux 6717 1

p92.1 Regurgitation and rumination in

newborn

136 1

f98.2 Feeding disorder of infancy and

childhood

4 11

r11.1 Vomiting 4313 2

r10.4 Colic 885 1

k59.0 Constipation (unspecified) 2471 3

k59.1 Functional diarrhea 5 6

r68.1 Excessive crying/fussy infant 1355 1

r14 Flatulence and related conditions 297 2

The reference cost of a NHS A&E visit in 2014/15 was £132. So the total cost of all

visits for infants in 2014/15 was £63.7 million. If all these visits by infants were due to

FGIDs then this is the upper bound of what the cost of A&E services due to FGIDs

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could be. If the percentage attending A&E due to gastrointestinal conditions is the

same regardless of age, this suggests that the cost of these infant visits is no higher

than £3.6 million.

Hospital Care - Outpatient data

The total number of outpatient appointments for the conditions of interest in 2014/15

was very small and were in single figures in some cases. For the two conditions with

the highest number of appointments – constipation and reflux – there were 4,000

episodes for all ages. Therefore, the number of appointments for children under 1

year of age would potentially be insignificant, from a cost perspective. However, in

95.5% of outpatient appointments the condition is recorded as unknown or

unspecified. Costs associated with outpatient care were excluded from the analysis

because we were unable to isolate the appointments from the dataset. Given there

were 85.6m outpatient appointments in England in 2014/15, if only a small

percentage of these were for infants with FGIDs the total costs would be substantial.

The exclusion of these appointments from the analysis is, therefore, a further

conservative element of the overall calculation.

Alternative therapies

The literature review highlighted that a range of alternative therapies, particularly for

infantile colic, had been considered across many countries. Such therapies include

chiropractic services, physiotherapy, homeopathy, osteopathy, and acupuncture. No

data were identified in the literature on the scale of use of these therapies. We

contacted professional associations and regulatory bodies associated with each

therapy to request any data they might hold on this issue. However, none were able

to provide information for the analysis. The costs of these approaches are therefore

not stated, which constitutes an underestimate of the real costs.

OTC colic remedies and special infant formulas

The total expenditure on colic remedies was £13.6 million and on anti-regurgitation

formulas was £9.6 million.

Estimated total cost infant FGIDs in England

Combining the different aspects of publicly funded and parental out of pocket

expenditure on infant FGIDs described above, we reached an overall estimate of the

COI of the conditions in England in 2014/15. This is summarised in Table 3. In total

the cost is estimated to have been £72.3 million.

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Table 3: Summary of costs of colic/FGID in England 2014/15

Cost Area Value (million)

Prescriptions of colic/reflux/constipation medicines £5.8

Prescriptions of colic/reflux/constipation formulas £0.9

Health visitor appointments £3.5

GP appointments (colic/reflux/constipation medicines and

formula)

£26.0

Admitted patient care £9.3

A&E visits £3.6

OTC colic medicines £13.6

OTC anti-regurgitation formulas £9.6

Total costs £72.3

DISCUSSION

There is compelling evidence of discrepancies between the guidelines for the

diagnosis and treatment of FGIDs, what physicians recommend, and what parents

may do. This systematic review has investigated the multitude of different treatments

and approaches to manage infant FGIDs that are used or have been trialled. Those

interventions reported in the systematic review may represent only a fraction of the

remedies that are being used on a daily basis. It is outside the scope of this review to

evaluate the efficacy of any intervention mentioned here, although for some OTC

remedies it appears that tolerance and safety data from clinical studies are lacking.

We hypothesized that the management of FGIDs is associated with considerable

expense and, in the absence of any complete COI dataset identified in the

systematic review, we chose England as the focus of a de novo COI calculation

because of the availability and quality of data on public and private healthcare

resource use.

Medicines or formulas prescribed in England to infants with FGIDs are free at the

point of consumption: the entire cost is borne by the NHS. The prescribed items

considered in this analysis, with the number and costs of prescriptions made in

England, are available from the HSCIC. The latest data available are from 2014/15

and cover prescriptions made in both primary and secondary care. However, the

taxpayer does not meet all the costs of healthcare in England. Most alternative

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therapies are not provided free of charge and medications that do not require a

prescription can be purchased at a pharmacy.

Our analysis has shown that the cost of FGIDs is substantial, costing a minimum of

£72.3 million in England in 2014/15 (£50 million to the NHS). This estimate is likely to

be significantly higher in reality since we have adopted a conservative approach in

our estimates.

Expenditure per capita on healthcare in England is amongst the lowest of all

developed countries. If this is the case for all age groups, then it would suggest that

the estimate for England is at the lower end compared to expenditure in other

developed countries for infants with FGIDs. Regardless, FGIDs are costly, both to

parents and to the NHS in England, with substantial expenditure on treatments for

which there is limited or no evidence of efficacy.

Our calculations are conservative both in the assumptions on which they are based

and the costs which have been excluded. The latter include:

I. alternative therapies,

II. diagnostic or treatment costs for admitted infants,

III. outpatient consultations,

IV. proton pump inhibitors,

V. days taken off work by parents or carers (absenteeism),

VI. reduced productivity of parents at work (presenteeism),

VII. costs associated with side effects from inappropriate interventions,

VIII. prescriptions of constipation remedies such as lactulose;

IX. prescriptions and OTC purchases of anti-allergy and comfort formulas for

infants that actually have an FGID.

These exclusions are both a strength and a limitation of the analysis. The exclusions

provide confidence that the estimated cost is a true lower bound of the actual cost,

but they result in an estimate that, by design, is not the true cost. The exclusions also

indicate areas where further research is required.

We estimated that the total yearly cost of therapies for FGIDs in infants in England

was £72.3 million excluding anti-allergy formulas. Records indicate that there are

approximately 700,000 newborns per year. If 30% of these infants experienced

FGIDs that required some kind of treatment, 210,000 infants per year would be

affected. Dividing the total costs per year by the number of affected infants we

estimate a cost of £348 per infant in the first year after birth.

It is likely that most of the care of infants for FGIDs is met in the primary and

community setting and this is borne out by the estimates. However, our estimates

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about the time spent by health visitors were based upon little actual data on resource

use but are, we consider, conservative.

It is not possible to determine whether all OTC medications purchased were

recommended by a physician, pharmacist or other health care professional. It was,

however, reported in another study conducted in 6 countries that overall, 17% of the

pediatric prescriptions were for herbal remedies and 15% were for homeopathic

preparations 55.

In conclusion, we found that FGIDs in infants generate substantial expense for

parents and the health care system. Our estimate is likely to be lower than the real

cost because of missing data and evidence.

The number of products sold to treat FGIDs suggested that some physicians do not

follow treatment guidelines. Some infants are being medicated unnecessarily, which

is potentially detrimental to patient health outcomes and definitely a wasted cost,

either to the taxpayer or to parents. This may be the consequence of parental

demands, but may also be a gap on the provision of parental reassurance.

Further research is required to understand why some physicians are choosing to

medicate and what strategies could be adopted such that doctors and parents can

manage symptoms by following clinical guidelines without resorting to costly

remedies and treatments with limited or no evidence on their effectiveness. The

potential cost savings and improved health outcomes are significant if such

strategies and options could be put in place.

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ACKNOWLEDGEMENTS

We would like to thank Dr. Sarah King (record selection and data extraction of

records for the systematic review), Anita Fitzgerald (systematic review report), and

Dr. Chris Marshall (record selection and data extraction of records for the systematic

review), for their support.

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Figure 1: PRISMA flow diagram for record selection process for systematic

review

SC

RE

EN

ING

IN

CL

UD

ED

E

LIG

IBIL

ITY

D

EN

TIF

ICA

TIO

N

Records identified through database searching

(n = 12364)

Additional records identified through other sources

(n = 78)

Records after duplicates removed

(n = 9479)

Records screened based on title and

abstract (n = 9479)

Records excluded after title and abstract

assessment (n = 9318)

Full-text documents assessed for eligibility

(n = 161)

Full-text documents excluded (n = 125)

Studies included in the review (n = 34)

reported in 35 papers

Unavailable potentially relevant studies not included in the review

(n = 1)

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Functional gastrointestinal disorders and related signs and symptoms in infants: discrepancies between actual and

estimated costs of recommended treatments in England

Journal: BMJ Open

Manuscript ID bmjopen-2016-015594.R1


Date Submitted by the Author: 28-Aug-2017

Complete List of Authors: Mahon, James; York Health Economics Consortium Lifschitz, Carlos; Hospital Italiano de Buenos Aires, Departamento de Pediatria

Ludwig, Thomas; Nutricia Research Thapar, Nikhil; Great Ormond Street Hospital For Children NHS Trust Glanville, Julie; University of York, York Health Economics Consortium Miqdady, Mohamad; Ped. GI, Hepatology & Nutrition Division Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates, Pediatrics Saps, Miguel; Nationwide Children’s Hospital, Columbus, Ohio, USA Seng Hock , Quak ; National University of Singapore, Singapore Lenoir-Wijnkoop, Irene; University of Utrecht, Utrecht, The Netherlands Edwards, Mary; University of York, York Health Economics Consortium Wood, Hannah; York Health Economics Consortium SZAJEWSKA, Hania; The Medical University of Warsaw, Dept of Paediatrics

<b>Primary Subject


Secondary Subject Heading: Gastroenterology and hepatology, Health economics



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Functional gastrointestinal disorders and related signs and symptoms in infants: discrepancies

between actual and estimated costs of recommended treatments in England















Word count: 3,603

Tables: 3

Online supplement: 1

Corresponding author: Carlos Lifschitz, M.D.

Hospital Italiano de Buenos Aires

Buenos Aires, Argentina

[email protected]

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ABSTRACT



Study design: To estimate the cost of illness (COI) of infant FGIDs a two stage

process was applied: a systematic literature review, and a COI calculation. As no

pertinent papers were found in the systematic literature review, a “de novo” analysis

was performed. For the latter, the potential costs for the third party payer (the

National Health Service (NHS) in England) and for parents/carers for the treatment of

FGIDs in infants were calculated, by using publicly available data. In constructing the

calculation, estimates and assumptions (where necessary) were chosen to provide a

lower bound (minimum) of the potential overall cost. In doing so, the interpretation of

the calculation is that the true COI can be no lower than that estimated.

Results: Our calculation estimated that the total costs of treating FGIDs in infants in




counter remedies.








implementation.

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Strengths

• The costs calculation is focused on more recent studies and data to ensure

currency and most recent practice are reflected in terms of care of FGIDs and

related signs and symptoms.

• Where necessary, estimates and assumptions were always chosen to provide

consistently a lower bound of the potential cost.

Limitations




calculation.

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review. HW, JMG and TL designed the search strategy. CL, HS, IL-W, MM, MS, and

SHQ gave input to the search strategy and the inclusion and exclusion criteria. JMG

and JM defined the data extraction elements. JM, JMG, ME, and TL wrote the

protocol, CL, JM, JMG, ME, and TL wrote this manuscript. CL, HS, IL-W, MM, MS,





James Mahon.








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ABBREVIATIONS


COI Cost of illness


GI Gastrointestinal









UK United Kingdom



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INTRODUCTION



and symptoms without obvious structural or biochemical alterations.[1] Within the first

year after birth, such symptoms can be observed in up to 50% of infants.[2, 3]



approximately 30%, 20%, and 15%, respectively.[4] In addition, many children may

present with a combination of FGIDs and related signs and symptoms.[3, 4] Although



professionals (HCPs).[3, 4]


and algorithms have been developed for their practical management by HCPs.[1, 4-

6] These algorithms build on parental support, reassurance, and nutritional advice as






other treatments that are either contraindicated or not substantiated scientifically.[7]



parents.

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METHODS

The study employed a two stage methodology to estimate the cost of illness (COI) of

infant FGIDs, a systematic literature review, and a COI calculation. Here, we report

in detail on the latter.

Stage One

A systematic literature review was undertaken to identify any studies published in or

after 2005 that provided information on a) the frequency and volume of reported

treatments of FGIDs and related signs and symptoms (regardless of their

effectiveness; b) costs to third party payers and/or parents of infants with FGIDs and

related signs and symptoms of prescribed treatments, over the counter (OTC) or

home remedies, visits to health care professionals and other providers of

complementary and other forms of care, and changes in infant formula; c) loss of

income for parents/carers of infants with FGIDs and related signs and symptoms, or

the specific symptom combinations described above, through inability to return to

work, time taken off work, and out of pocket costs.




details of the review methods and protocol have been published in detail.[8] Studies



Stage Two –COI calculation for one country

Since the systematic review identified no research on COI for any country, we

performed a calculation for one country using evidence from stage one (the literature

review) where appropriate, and from readily available data sources. England was

chosen as an exemplar country due to the availability and quality of data on

healthcare resource use, both publicly and privately, and the availability of these data

in the English language.






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Prescription data























months.





been proven to be ineffective [9] and have frequent side effects.[10-12]








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9







between 10% and 40%.[13] A National Institute of Health Research funded ongoing

trial of supporting parents of infants with colic indicates an incidence of 1 in 5

infants.[14] Applying the 1 in 5 figure to the 697,852 infants born live in England and

Wales in 2015 means that approximately 140,000 infants in England experienced

colic in that year.











Hospital care













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for FGIDs.















the period 2014/15.

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11

RESULTS


The full review results are presented in the in a supplement to this manuscript

(Supplementary File). In total, 12364 records were identified from database

searching and 78 from additional resources. After the steps of duplicate removal,

title, abstract, and full text screen, 31 studies were identified that provided data about

treatments, signs and symptoms of FGID in infants. 3 further studies provided

additional data on young children in the USA.[15-17] 26 of the 31 eligible studies

were randomized controlled trials and five were case series.[8] Almost half (15) of

these studies were undertaken in Europe [18-32] (including three in the UK).[30-32]

Four studies were conducted in the USA [33-36], three in Australia [37-39], three in

Turkey [40-42], and one each in Brazil [43], Canada [44], China [45], Iran [46], Israel

[12] and Nigeria [47]. Twenty nine studies included infants with infantile colic and two

studies included infants with constipation. Several different interventions were

addressed in the eligible studies. We could not identify any study that addressed the

whole spectrum of costs of treating FGID in infants.

Stage Two –COI calculation for England

Prescription data







of £0.9 million.



Cost £ (millions)

Medicinal 521.2 5.8 Colic 115.1 1.1

Colief_Infant Dps 64.7 0.9 Dentinox_Infant Colic Dps 3.1 <0.1

Infacol_Susp 40mg/ml S/F 47.1 0.2 Nurse Harveys_Gripe Mix <0.1 <0.1 Woodward's_Gripe Water 0.2 <0.1

Constipation 24.8 <0.1 Glycerol Suppository Infants (1g) 23.9 <0.1

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Cost £ (millions)


0.9 <0.1

Reflux & Regurgitation 381.4 4.7 Gaviscon Infant_Sach 2g (Dual Pack) S/F (9/10 of total prescriptions)

381.4 4.7

Colic and regurgitation formulas 58.8 0.9 Reflux & Regurgitation 55.8 0.8 Colic 3.0 0.1

Grand Total 580.0 6.7



minutes, with a unit cost per half hour of £25[48] giving a cost of £3.5 million.



equate to a cost to the NHS of £26.0 million.[48] For the allergy and other special

infant formulas the cost of GP time would be £30.9 million.






2014/15 was £359.13.[49] The total cost of the admitted patient care was therefore

£9.3 million. This cost is only for bed days and does not include the cost of any

diagnostic procedures.




conditions was 5.7%.[50] We estimated the number of attendances due to GI

conditions in infants aged under one year by assuming that the proportion of

attendances due to GI conditions is the same across age groups. Evidence from the

USA identified in the literature review suggested that 9.4% of all Emergency

Department visits in the USA due to constipation were in those aged under 12

months. [16] If a similar pattern is seen in England, and for all FGIDs, then this

means that the estimated attendances we have calculated are likely to be a

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13

significant underestimate.



ICD10

code


admissions

Mean length of

stay

k21.9 Reflux 6717 1


newborn

136 1


childhood

4 11


r10.4 Colic 885 1





The reference cost of a NHS A&E visit in 2014/15 was £132.[49] So the total cost of

all visits for infants in 2014/15 was £63.7 million. If all these visits by infants were due

to FGIDs then this is the upper bound of what the cost of A&E services due to FGIDs



than £3.6 million.












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chiropractic services, physiotherapy, homeopathy, osteopathy, and acupuncture.[24,

27, 28, 30, 31] No data were identified in the literature on the scale of use of these

therapies. We contacted professional associations and regulatory bodies associated

with each therapy to request any data they might hold on this issue. However, none

were able to provide information for the analysis. The costs of these approaches are

therefore not stated, which constitutes an underestimate of the real costs.















formula)

£26.0


A&E visits £3.6



Total costs £72.3

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15

DISCUSSION



may do. Our systematic literature review reports a multitude of different treatments


reported interventions may still represent only a fraction of the remedies that are

being used on a daily basis. It is outside the scope of this review to evaluate the

efficacy of any intervention mentioned here, although for some OTC remedies it

appears that tolerance and safety data from clinical studies are lacking.



systematic literature review, we chose England as the focus of a COI calculation


resource use.












our estimates.


developed countries.[51] If this is the case for all age groups, then it would suggest

that the estimate for England is at the lower end compared to expenditure in other









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16











indicate areas where further research is required.















preparations.[52]




The number and type of products sold to treat FGIDs suggested that some

physicians do not follow treatment guidelines. Some infants are being medicated

unnecessarily, which is potentially detrimental to patient health outcomes and

definitely a wasted cost, either to the taxpayer or to parents. This may be the

consequence of parental demands, but may also be a gap on the provision of

parental reassurance. These findings support the impression of those co-authors

who are paediatric gastroenterologists practicing in different parts of the world (CL,

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NT, MM, MS, SHQ, HS) who see in consultation infants with FGIDs who frequently

have been treated not in accordance to guidelines.







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ACKNOWLEDGEMENTS





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28. Reinthal M, Andersson S, Gustafsson M, et al. Effects of minimal acupuncture in children with infantile colic - A prospective, quasi-randomised single blind controlled trial. Acupunct Med 2008;26:171-82.

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47. Oshikoya KA, Senbanjo IO, Njokanma OF. Self-medication for infants with colic in Lagos, Nigeria. BMC Pediatr 2009;9:9.

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1

SUPPLEMENTAL MATERIAL TO

Functional gastrointestinal disorders and related signs and

symptoms in infants: discrepancies between actual and estimated

costs of recommended treatments in England

Authors: James MAHON1*

, Carlos LIFSCHITZ2*

, Thomas LUDWIG3, Nikhil THAPAR

4, Julie GLANVILLE

1,

Mohamad MIQDADY5, Miguel SAPS

6, Seng Hock QUAK

7, Irene LENOIR-WIJNKOOP

8, Mary EDWARDS

1,

Hannah WOOD1, Hania SZAJEWSKA

9


1 York Health Economics Consortium, University of York, York, UK 2 Hospital Italiano, Buenos Aires, Argentina 3 Nutricia Research, Singapore 4 Great Ormond Street Hospital, London, United Kingdom 5 Pediatric Gastroentrology, Hepatology & Nutrition Division Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates 6 Nationwide Children’s Hospital, Columbus, Ohio, USA 7 National University of Singapore, Singapore 8 University of Utrecht, Utrecht, The Netherlands 9 Medical University of Warsaw, Warsaw, Poland

The systematic review protocol is published in:

Glanville J, Ludwig T, Lifschitz C, Mahon J, Miqdady M, Saps M, Hock Quak S, Lenoir-

Wijnkoop I, Edwards M, Wood H, Szajewska H. Costs associated with functional

gastrointestinal disorders and related signs and symptoms in infants: a systematic review

protocol. BMJ Open. 2016 Aug 24;6(8):e011475. doi: 10.1136/bmjopen-2016-011475

This document presents the results of the systematic review.

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https://www.ncbi.nlm.nih.gov/pubmed/27558903




Abbreviations

AACP Acupuncture Association of Chartered Physiotherapists

ALSPAC Avon Longitudinal Study of Parents and Children

AWMA Academy of Western Medical Acupuncture

BMAS British Medical Acupuncture Society

BMJ British Medical Journal

CAM Complementary and Alternative Medicine

CEA Cost Effectiveness Analysis

CMP Cows' Milk Protein

COI Cost of Illness

COL Cost of living

CRD Centre for Reviews and Dissemination

DARE Database of Abstracts of Reviews of Effects

EED Economic Evaluation Database

ESPGHAN European Society for Pediatric Gastroenterology, Hepatology, and Nutrition


GER Gastro-esophageal Reflux

GERD Gastro-esophageal Reflux Disease

GOR Gastroesophageal Reflux

GORD Gastroesophageal Reflux Disease

GSRS Gastrointestinal Rating Scale


HTA Health Technology Assessment

IBS Irritable Bowel Syndrome

ISPOR International Society for Pharmacoeconomics and Outcomes Research

JAMA Journal of the American Medical Association

NASPGHAN North American Society for Pediatric Gastroenterology, Hepatology, and

Nutrition

NHS National Health Service

NICE National Institute for Health and Care Excellence

OTC Over the Counter

PLOS Public Library of Science

PPI Proton Pump Inhibitor

PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses

RCT Randomised Controlled Trial

REPEC Research Papers in Economics

REST Reassurance, Empathy, Support, Time out



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Section 1: Results of the Systematic Review

1.1 LITERATURE SEARCH RESULTS

The searches identified 12,442 records (Table 1.1). Following deduplication 9,479 records

were assessed for relevance.

Table 1.1: Literature search results by resource

Resource or study identification method Number of records identified

MEDLINE and MEDLINE In-Process 2793

PubMed (for non-MEDLINE records only) 1395

Embase 6500

PsycINFO 746

NEXIS 528

Database of Abstracts of Reviews of Effects (DARE) 109

Health Technology Assessment Database (HTA Database) 11

NHS Economic Evaluations Database (NHS EED) 25

CEA Registry 0

NHS Evidence Search 16

OAISTER 240

RePEc 1

Conference hand-searches 24

Contacting conference abstract authors 8

Checking reference lists 45

Other 1

Total number of records 12,442

Total number of records following deduplication 9,479

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Figure 1.1: Record selection process (PRISMA)

SC

RE

EN

ING

IN

CL

UD

ED

E

LIG

IBIL

ITY

D

EN

TIF

ICA

TIO

N

Records identified through database

searching

(n = 12364)

Additional records identified through

other sources

(n = 78)


(n = 9479)

Records screened based

on title and abstract

(n = 9479)

Records excluded after title

and abstract assessment

(n = 9318)

Full-text documents

assessed for eligibility

(n = 161)

Full-text documents

excluded

(n = 125)

Studies included in the

review

(n = 34)


Unavailable potentially

relevant studies not included

in the review

(n = 1)

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1.2 STUDY CHARACTERISTICS

34 studies (reported in 35 documents) were identified reporting treatments for FGIDs and as

well as related signs and symptoms, in infants younger than one year of age. One study

was reported in two documents [1, 2]. Full details of the study characteristics of the included

studies are reported in Table 1.2.

1.2.1 Study design

26 of the 34 studies (77%) were RCTs [2-27], including two crossover trials [4, 7] and a

quasi-randomised trial [19]. Three of the studies [28-30] were cost of illness studies,

although only of specific aspects of interventions for infant FGID. The remaining five studies

were cohort, case series and cross sectional studies [31-35].

1.2.2 Study location

Almost half (15/34) [2, 7, 8, 11-13, 19, 21-25, 27, 33, 34] of the included studies were

conducted in Europe, including three in the UK [8, 13, 34]. Seven studies were conducted in

the USA [6, 10, 15, 20, 28-30] ; three in Australia [14, 16, 26]; three in Turkey [3, 5, 32]; and

one each in China [17], Brazil [4] , Israel [31], Canada [9], Iran [18] and Nigeria [35].

1.2.3 Perspective

Of the 34 included studies, the majority assessed data from a patient/parent and healthcare

perspective (32/34, 94%). Two studies assessed data from only the patient/parent

perspective [19, 32].

1.2.4 Study objectives

Study objectives varied across the 34 included studies, but the majority sought to evaluate

an intervention in infants with colic or functional constipation.

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Table 1.2: Systematic review: Study characteristics

Study reference

Country Study design

Perspective Primary study objectives Study

duration Inclusion criteria

Akcam 2006 [3]

Turkey RCT Patient and healthcare provider

To study efficacy of 30% glucose solution in the treatment of infant colic

Mar – Dec 2003

“Typical infant colic” – minimum of 3h crying per day, 3 days per week for the last 3 weeks

Alves 2012 [4]

Brazil RCT Patient and healthcare provider

To compare the efficacy of Mentha piperita with

simethicone in the treatment of infant colic

Mar – Dec 2011

Infants aged 15 to 60 days, exclusively breastfeeding. IC was characterised as

paroxysmal attacks or irritability, restlessness, or crying for at least 3 hours a day, and

occurring more than 3 days a week for a period of 3 weeks

Arikan 2008 [5]


To evaluate the effectiveness of massage, sucrose solution,

herbal tea or hydrolysed formula, each used individually

in the treatment of infantile colic

Jan – Jun 2005

Infant between 4–12 weeks of age with typical infantile colic as defined by Wessel et al.; born

at term or preterm (gestational age 37–42 weeks) with a birth weight between 2.5 and 4

kg; appropriate gain in weight, length and head circumference and normal psychomotor

development on paediatric physical examination

Aviner 2010 [31]

Israel Case series Patient and healthcare provider

To report on 11 infants who presented with an apparent life-

threatening event after ingestion of Gali-col Baby, a homeopathic agent indicated

for “infantile colic”

Jan 2005 – Aug 2008

A computerised search was conducted for admissions with 1 of the following diagnoses:

apparent life-threatening event, apnea, choking, cyanotic spell or episode, and sudden infant death syndrome (of these 11 patients were

found to have taken Gali-col)

Berseth 2009 [6]

USA RCT Patient and healthcare provider

To examine the effects of a partially hydrolysed cow’s milk protein, low lactose formula or

a soy-based lactose-free formula on infant fussiness

(defined as general irritability, discontentment, or discomfort that is difficult to soothe) and other symptoms of formula

intolerance (crying, gas, occurrences of spit-up,

diarrhoea, constipation, and

NR

Singleton births, 7-63 days of age, with a minimum birth weight of 2500 g, solely received a full-lactose, intact cow’s milk protein formula

for 7 days before randomisation, and were parent-identified as very fussy or extremely fussy in the baseline tolerance evaluation

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stool patterns) in term infants parent identified as very or

extremely fussy

Bongers 2007 [7]

The Netherlands

RCT Patient and healthcare provider

To examine the effects of a new infant formula in constipated infants

Apr 2002 – Jan 2004

Otherwise healthy, term infants with constipation, between 3 – 20 weeks of age, who received at least 2 bottles of milk-based formula

per day

Browning 2008 [8]

UK RCT Patient and healthcare provider

To compare the short-term effects of chiropractic spinal manipulation and occipito-

sacral decompression in the treatment of infant colic

NR

Less than 8 weeks of age, born with birth weight equal to or more than 2500 g, born at or after 38 weeks gestation, cry for 3 h or more per

day with one or more inconsolable crying episodes for at least four of the previous 7 days and show typical restless behaviour (i.e. motor

unrest, flexing knees against abdomen, extending the trunk, neck, and extremities). The parent/guardian had to be fluent and

literate in the English language.

Chau 2015 [9]

Canada RCT Patient and healthcare provider

To investigate the effectiveness of Lactobacillus reuteri DSM 17938 for the treatment of infantile colic in breastfed

infants, compared with placebo

Feb 2012 – Apr 2014

Diagnosis of infantile colic (i.e, crying or fussy/gassy episodes ≥3 hours/day for ≥3

days/7 days, as defined by a modified definition of Wessel criteria); age 3 weeks to 6 months;

exclusively breastfed; term delivery (≥37 weeks gestation at birth); 5-minute Apgar score ≥7;

and birth weight ≥2500 g

Ciftci 2007 [32]

Turkey Cross

sectional Parents

To assess the methods used by mothers to eliminate colic in their infants and to determine

the efficacy of the various methods

Jan –Feb 2005

Infants aged 1–3 months registered at a primary health centre

Cirgin 2006 [10]


To examine the effect of using Dr. Brown’s Natural Flow baby bottles to feed the colicky infant on the mean time per day the infant spent crying, fussing,

and sleeping

NR 7 months old or less and receiving the majority

of their feedings by bottle

Coccorullo Italy RCT Patient and To evaluate the beneficial Jan – Dec Formula-fed infants >6 months of age referred

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2010 [11] healthcare provider

effects of Lactobacillus reuteri (DSM 17938) in infants with

functional chronic constipation

2008 for functional chronic constipation to the Gastrointestinal Endoscopy and Motility Unit of

the Department of Pediatrics, University ‘‘Federico II’’ of Naples

Dupont 2010 [12]

France RCT Patient and healthcare provider

To evaluate the nutritional adequacy, the gastrointestinal

tolerance and the effect on colic of an α-lactalbumin-enriched and probiotic-

supplemented infant formulae, in infants with colic

NR

Infants had to be born at term, aged 3 weeks to 3 months, weaned, with normal growth and with more than 3 weeks of crying periods, at least 3 h per day, 3 days per week (Wessel et al., 1954 [36]), with or without abdominal distension, gas

and regurgitation

Hayden 2006 [13]


To investigate the effect of cranial osteopathic

manipulative treatment on the pattern of increased crying,

irritability and disturbed sleep associated with infantile colic

NR

Infants between 1 and 12 weeks of age, not been previously treated osteopathically,

exhibited signs of infantile colic and no signs or symptoms indicative of other disease

Hill 2005 [14]

Australia RCT Patient and healthcare provider

To evaluate the effect of a hypoallergenic maternal

elimination diet on persistent crying among breastfed infants

presenting with colic

2000 – 2002

Exclusively breastfed infants <6 weeks of age with colic; well, term infants (gestational age of

37 weeks) who were the result of a normal singleton pregnancy

Infante Pina 2008

[33] Spain

Cross sectional

Patient and healthcare provider

To assess the effectiveness of dietetic treatment with the Novalac range of formulas

specifically developed for mild gastrointestinal disorders.

NR

Infants up to four months of age fed with artificial milk formulas; the presence of mild gastrointestinal disorders; the possibility of

feeding the infants with some product of the Novalac line of formulas; continuation of these formulas on an exclusive basis for at least 30

days.

Keefe 2006 [15]


To evaluate an individualized intervention program for infant

irritability or colic NR

Full term, healthy low-risk infants between the ages of 2 and 6 weeks, and living within a 2-

hour radius of the metropolitan area.

Kianifar 2014 [16]


To determine efficacy of synbiotic in reducing average infant crying time at day 7 and

day 30 after starting

NR

Healthy breastfed infants aged 2 weeks to 4 months with infant colic defined as per Wessel’s criteria based on care giver’s symptom records

diary.

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intervention

Landgren 2010 [2]

Sweden RCT Patient and healthcare provider

To investigate whether acupuncture reduces the

duration of crying in infants with colic

Nov 2005 – Feb 2007

Healthy infants, born after gestational week 36, not treated with dicyclomine and fulfilling the

modified Wessel criteria for colic: ‘crying/fussing for at least 3 hrs a day, occurring 3 days or

more in the same week’

Mi 2015 [17]

China RCT Patient and healthcare provider

To explore the role which L. reuteri could play in the

management of infant colic

Feb 2013 – Apr 2014

Infants less than 4 months of age weighing between 2.5 and 4kg and exclusively or

predominantly breastfed

Miller 2012 [34]

UK Cohort Patient and healthcare provider

To determine any possible justification of the use of three

priori clinically determined categories of excessively crying infants, based on

differences in parent reported outcomes after a course of

chiropractic treatment

Jul 2007 – Mar 2008

All babies between the ages of one day and 18 weeks who presented with excessive crying to a

UK chiropractic teaching clinic between July 2007 and March 2008

Infants included if they could be categorised

using clinical signs and symptoms into one of the three classification groups; infant colic, irritable Infant syndrome of musculoskeletal origin or inefficient feeding crying infant with

disordered sleep.

Moravej 2010 [18]

Iran RCT Patient and healthcare provider

To investigate the value of skin prick testing (SPT) in the

diagnosis of cow’s milk allergy in patients with infantile colic

NR Breast-fed infants with history of infantile colic

(diagnosed based on the Wessel criteria) between the ages of 3 weeks and 3 months

Oshikoya 2009 [35]

Nigeria Cross

sectional


To determine the knowledge of Nigerian mothers about colic,

their home-based management, extent of self-

medication for the infants with colic and the types of medicines involved

Apr – Sep 2006

Mothers who brought their infants for vaccination to a primary health care centre

Park (2015)

USA

COI (retrospective

database analysis)

Healthcare provider

To analyze the inpatient burden of common childhood FGIDs

including constipation, abdominal pain, IBS, dyspepsia, abdominal

1997-2009

All infants in whom constipation, abdominal pain, dyspepsia, IBS, abdominal migraine, fecal

incontinence was the primary discharge diagnosis from 1997, 2000, 2003, 2006 and

2009

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migraine, and fecal incontinence

Reinthal 2008 [19]

Sweden RCT Patient

To evaluated the effects of light needling on crying and the pain

related behaviour in children with infantile colic

NR

New born, breastfed children with infantile colic (as described by Wessel et all, 1954 [36])

diagnosed by doctors and registered at one of 21 Child Welfare Clinics within an area of

western Sweden.

Salisbury 2012 [20]


To examine the effectiveness of a unique model of integrated care for the treatment of infant

colic.

NR

Participants were largely self-referred after seeing brochures in the office of their

healthcare provider or were referred from a Specialty Clinic. Infants were required to be:

singleton, born at or after 37 weeks gestational age, aged 4 to 8 weeks of age at the time of

enrolment, had no more than 4 days of special nursery care after birth, no congenital

anomalies, no exposure to illegal drugs in utero, and no suspicion of foetal alcohol syndRome. The family needed to be English-speaking and

have a working telephone in the home. Mothers were over 17 years old and had no

history of psychiatric hospitalization or involvement with Child Protective Services.

The infant needed to be otherwise healthy, and meet the “Wessel Rule of 3s” criteria by parent report at the time of the call: crying for at least 3 hr a day for at least 3 days a week for at least 3

weeks.

Savino 2015 [21]

Italy RCT Patient and healthcare provider

To evaluate the efficacy of orally administered L. reuteri DSM 17938 with vitamin D3 from the age of ten days in

reducing parental discomfort due to infantile colic in a

population of otherwise healthy infants.

2012 - 2013

New borns aged less than 10 days of life, with gestational age between 37 and 42 weeks, birth

weight from 2,500 to 4,300 g, and normal physical examination

Savino Italy RCT Patient and To test the efficacy of 2008 - 2009 Breast fed infants diagnosed with infantile colic

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Lactobacillus reuteri on infantile colic and to evaluate its relationship to the gut

microbiota

according to the following modified Wessel’s criteria: episodes of fussy crying that lasted 3

hours a day and episodes that lasted for 3 days in the 1 week before enrolment. All were born

at term, adequate for gestational age (birth weight: 2500 – 4000 g), and aged 2 to 16 weeks at recruitment. Only exclusively

breastfed infants were enrolled to prevent variability in the intestinal microbiota caused by

diet.

Savino 2006 [23]


To confirm the role of new formula in colicky infants with a

randomized prospective controlled trial.

2002 - 2003

Gestational age between 37 and 42 weeks, normal birth weight (>2500 g), regular weight

gain (>=150 g/week) and normal physical examination

Savino 2007 [24]


To test the hypothesis that oral administration of Lactobacillus

reuteri in a prospective randomized study would

improve symptoms of infantile colic.

2004 - 2005

Breastfed infants with a diagnosis of infantile colic Patients 21 to 90 days of age, appropriate for gestational age with birth weights between

2500 and 4000 g, with colic symptoms ( 3 hours of crying on 3 days in the week) with debut 6

+/-1 days before enrolment

Sethi (2014)

USA

COI (retrospective

database analysis)

Heatlhcare provider

To evaluate patient admission rates, length of stay and costs

for constipation in the USA 1997-2010

Any admission with ICD-9-CM primary diagnostic codes 564.0-564.9

Skjeie 2013 [25]

Norway RCT Patient and healthcare provider

To test the hypothesis that acupuncture treatment has a clinically relevant effect for

infant colic

2009 - 2012 Fulfilled Wessel’s criteria [36] and were born at

full term.

Sommers (2015)

USA

COI (retrospective

database analysis)

Heatlhcare provider

To evaluate ED visits and costs for constipation in the USA

2006-2011 Any admission with ICD-9-CM primary

diagnostic codes 564.0-564.9

Sung 2014 [26]


To determine whether the probiotic Lactobacillus reuteri DSM 17938 reduces crying or fussing in a broad community

2011 - 2012

Healthy term infants less than 13 weeks of age with infant colic, defined by modified Wessel’s criteria of crying or fussing for three hours or

more a day for three days or more over seven

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based sample of breastfed infants and formula fed infants

with colic aged less than 3 months

days. Fussing was defined as “behaviour that is not quite crying but not awake and content

either.”

Szajewska 2013 [27]

Poland RCT Patient and healthcare provider

To determine whether administration of Lactobacillus

reuteri (L reuteri) DSM 17938 is beneficial in breastfed infants

with infantile colic

2010 - 2011

Full term infants aged <5 months with infantile colic (defined as crying episodes lasting 3 or more hours per day and occurring at least 3

days per week within 7 days prior to enrolment), who were exclusively or predominantly (>50%)

breastfed.

Key: ED – Emergency department; RCT: Randomised controlled trial; USA: United States of America; CMP: Cows’ Milk Protein; COI: Cost of illness

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1.3 PARTICIPANTS’ CHARACTERISTICS

1.3.1 Number of trial participants

Of the 26 RCTs [2-27], nine [3, 4, 7, 8, 10, 11, 13, 17, 19] included fewer than 50

participants; ten trials [2, 9, 12, 16, 18, 20, 22, 24, 25, 27] included between 50 and 100

participants and seven trials [5, 6, 14, 15, 26, 32, 34] included between 101 and 200

participants.

Of the five case series studies, study numbers ranged from 11 [31] to 1441 [33]. Two case

series studies included between 150 and 190 patients [32, 34] and another included 800

patients [35].

1.3.2 Age

All included studies were required to investigate treatments, signs and symptoms in infants

less than 12 months old. The youngest participant was one day old, and the eldest was 12

months old. One COI study included patients aged over 12 months but data for patients

under 12 months of age could be isolated in the analysis [30].

1.3.3 Sex

Among the studies that reported the number of males overall, the percentage of males

ranged from 36% [31] to 79% [13] with an average percentage of males of 53%.

Among the studies that reported the number of males for treatment and control groups

separately, treatment groups ranged from 44% [26] to 65% [19, 27] males, while control

groups had from 48% [20, 21, 23] to 59% [26] males.

Four studies did not report the number of males [4, 12, 16, 18].

1.3.4 FGID description

The majority of studies (27/34, 80%) included participants with infantile colic. Four studies

included participants with constipation [7, 11, 28, 29], one had participants with a range of

FGIDs including constipation and dyspepsia [30] and one trial described participants as

having mild gastrointestinal disorders including colic, regurgitation, diarrhoea and

constipation [33].

1.3.5 ROME criteria met

Seventeen of the 34 included studies met the ROME III criteria (17/34, 50%) [4, 7-9, 11, 12,

14, 20, 22-26, 28-30], seventeen studies did not explicitly meet the ROME III criteria.[2, 3, 5,

6, 10, 13, 15-18, 21, 31, 33-35].

Full details of the participants’ characteristics are reported in Table 2.3..

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Table 1.3: Systematic review: Participants’ characteristics

Study ID Number of participants Age Sex

FGID description ROME III criteria Min age Max age % = Male

Akcam 2006 [3]

25 Randomised 28

Analysed (16 Treatment, 12 Control)

NR NR Overall: 48% Infantile Colic No

Alves 2012 [4] 30 8 days 56 days NR Infantile Colic Yes

Arikan 2008 [5] 175

(35 x 4 treatment groups, 35 control)

4 weeks 12 weeks Overall: 55% Infantile Colic No

Aviner 2010 [31] 11 Treatment,

11 matched controls 14 days 49 days Overall: 36% Infantile Colic No

Berseth 2009 [6] 159

(82 Treatment A, 77 Treatment B)

7 days 63 days Overall: 48% Infantile Colic No

Bongers 2007 [7] 38

(20 Treatment, 18 Control)

0.7 months 5 months Overall: 50% Constipation Yes

Browning 2008 [8] 43


NR 8 weeks Overall: 63% Infantile Colic Yes

Chau 2015 [9] 52


31 days 51 days Overall: 48% Infantile Colic Yes

Ciftci 2007 [32] 186 1 month 3 months Overall: 52% Infantile Colic Unclear

Cirgin 2006 [10] 36 NR 7 months Overall: 48% Infantile Colic No

Coccorullo 2010 [11]

44 (22 Treatment,

22 Control) 6 months NR Overall: 55% Constipation Yes

Dupont 2010 [12]

66 Randomised, 47 Analysed


3 weeks 3 months NR Infantile Colic Yes

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Study ID Number of participants Age Sex FGID description ROME III criteria

Hayden 2006 [13]




Hill 2005 [14]



2.9 weeks 8.6 weeks Overall: 60% Infantile Colic Yes

Infante Pina 2008 [33]

1441 1 week 4 months Overall: 52%

Mild-gastrointestinal disorders including colic, regurgitation, diarrhoea

and constipation

No

Keefe 2006 [15] 121 2.6 weeks 7.7 weeks Overall: 50% Infant irritability; Colic No

Kianifar 2014 [16] 50


2 weeks 4 months NR Infantile Colic No

Landgren 2010 [2]

90 Randomised (46 Treatment,

44 Control)

81 Analysed (43 Treatment,

38 Control)


Mi 2015 [17]

42 Randomized (21 Treatment 21 Placebo);

39 Analysed

(20 Treatment, 19 Placebo)

Mean: 29.7 days 4 months Overall: 56% Infantile Colic No

Miller 2012 [34]

158 (Colic = 77;

Infant syndrome of musculoskeletal origin =

56; inefficient feeding crying

infant with disordered sleep

1 day 18 weeks Overall: 57%

Infant colic, irritable Infant syndrome of

musculoskeletal origin or inefficient feeding crying


No

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Study ID Number of participants Age Sex FGID description ROME III criteria = 25)

Moravej 2010 [18] 77

(35 Treatment, 42 controls)


Oshikoya 2009 [35]

800 Mothers: 15 years

old Infants: 1 day

Mothers: 40 years old

Infants: 12 months Overall: 52% Infantile Colic No

Park (2015) [30]

4,436,817 discharges in 1997;

4,600,709 discharges in 2009

0 to 12 months 51% (all ages)

Functional GI disorders: chronic constipation,

abdominal pain, irritable bowel syndrome,

dyspepsia, abdominal migraine, fecal incontinence

Yes

Reinthal 2008 [19]

40 (20 Treatment,

20 Control)

Treatment: 1 week Control: 3 weeks

Treatment: 11 weeks

Control: 25 weeks

Treatment: 65% Control: 55%

Infantile Colic No

Salisbury 2012 [20]

62 (31 Treatment,

31 Control) 4.1 weeks 10.5 weeks


Infantile Colic Yes

Savino 2015 [21] 105


NR Overall: <10 days Treatment: 49%

Control: 48% Infantile Colic No

Savino 2010 [22] 50


NR: median treatment:

32.5 days (21) Control: 28.5 days

(21)

NR Treatment: 60%

Control: 56% Infantile Colic Yes

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Savino 2006 [23]

267 Randomised, 199 Analysed (96 Treatment, 103 Control)

Treatment: mean 1.39 months (±0.84) Control: mean 1.29

months (±0.77)

NR Treatment: 52%


Savino 2007 [24]

90 Randomised 83 Analysed


Treatment: 11 days Control: 14 days

Treatment: 80 days

Control 74 days


Infantile Colic Yes

Sethi 2014 [29] 20% of admitted population

in 12 months 0-12 months

38% 1997 39% 2010

Constipation (ICD-9-CM codes 564.0-564.9)

Yes

Skjeie 2013 [25] 84


Treatment: 3 weeks Control: 3 weeks

Treatment: 13 weeks

Control: 9 weeks


Infantile Colic Yes

Sommers 2015 [28]

20% of all ED visits in 12 months

0-12 months NR Constipation (ICD-9-CM

codes 564.0-564.9) Yes

Sung 2014 [26]


82 Control); 127 Analysed

Treatment: mean 7.5 weeks (±2.9)

Control: mean 6.9 weeks (±2.5)

NR Treatment: 44%


Szajewska 2013 [27]

80 (40 Treatment,

40 Control)


Treatment: 81 days

Control: 69 days


Infantile Colic Yes

Key: NR: Not reported

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1.4 INTERVENTIONS AND COMPARATORS

1.4.1 Intervention

Several different interventions were investigated across the 31 included studies that

considered interventions.

Ten studies investigated the impact of probiotic supplementation [9, 11, 12, 16, 17,

21, 22, 24, 26, 27];

Four studies used particular types of infant formula [6, 7, 23, 33];

Three studies used multiple types of interventions (alone or in combination) [5, 32,

35];

Three studies used acupuncture [2, 19, 25];

Three studies used chiropractic treatment [8, 13, 34];

Two studies changed the maternal diet [14, 18];

Two studies used natural remedies [4, 10];

One study used glucose [3];

Two studies used parental counselling [20];

One study used a homeopathic remedy [31].

1.4.2 Adverse events from an intervention

The majority of intervention studies reported that there were no side effects (15/31) from the

intervention under investigation, or did not report whether patients experienced any side

effects (12/31).

Four studies reported side effects associated with interventions. One study investigated

adverse events in infants receiving Gali-col Baby, a homeopathic remedy, and showed that 9

of the 11 participants had at least two adverse event symptoms [31].

Three studies investigating formulas reported side effects; in one study a soy based formula

was associated with adverse events in 50% of participants [6] while a second study

investigated a range of formulas belonging to the Novalac line (Anti-Colic, Anti-

Regurgitation, Anti-Diarrhoea, Anti-Constipation) and reported that 3.9% of infants suffered

an adverse event, most frequently affecting the digestive tract (1.4%), including diarrhoea

and constipation.[33] In a third study, a probiotic enriched formula reportedly caused

gastrointestinal side effects in 44% of infants and 15% experienced feeding-related side

effects.[12]

1.4.3 Comparator

Of the 26 RCTs with comparator groups, nine trials compared their interventions with

placebo [3, 9-11, 16, 17, 22, 25, 27]; eight compared interventions to standard care [2, 7, 12,

14, 15, 18-20]; seven compared their interventions to an alternative intervention [4, 6, 8, 21,

23, 24, 26] and two used no comparator intervention [5, 13].

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1.4.4 Adverse events from the comparator treatment

Three studies reported side effects associated with comparator treatments.[6, 12, 22] One

study investigated adverse events in 77 infants randomised to a comparator group who

received a partially hydrolysed cow’s milk protein, low lactose formula. 44 participants (58%)

had at least one adverse event [6].

A second study investigated adverse events in 24 infants randomised to a comparator group

who received a control formula (not enriched with probiotics as per the intervention) and

found that 67% of the comparator group experienced GI side effects including constipation,

vomiting, colitis, regurgitation and flatulence [12].

A third study investigated adverse events in 25 infants randomised to a placebo comparator

group. Compared to the one infant in the probiotic intervention group who developed rhinitis,

four infants in the placebo group experienced an adverse event including eczema, fever,

otalgy and gastroesophageal reflux [22].

1.4.5 Length of treatment

The length of treatment varied across the included studies, but overall ranged from one to

four weeks.

Full details of the interventions and comparators of the included studies are reported in

Table 1.4.

1.4.6 Cost of illness studies

Two of the cost of illness studies reported on hospital care for infants with functional

constipation [28, 29] in the United States based upon retrospective analysis of a database

covering 20% of all admissions and ED attendances. One study [28] reported 50,934 ED

attendances for infants with constipation at a cost of $2470 per attendance – although the

cost was based upon all attendances for adults and children. The second study [29] reported

499 hospital admissions for infants with constipation in 2010 at a cost of $17,518 per

admission but again this cost was for children and adults.

The third cost of illness study [30] also reported an analysis of a large databse of hospital

admissions, but for a range of FGIDs including constipation and abdominal pain. The rate of

discharge for infants aged under 12 months was 0.8 per 10,000 discharges for constipation,

1.0 per 10,000 discharges for abdominal pain and 0.1 per 10,000 discharges for dyspepsia.

Costs per discharge were provided but covered all patient under 18 years of age. Details of

the cost of illness studies are reported in Table 1.5.

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Table 1.4: Systematic review: details of interventions and comparators

Study ID Intervention Treatment dosing

and frequency Adverse events from treatment

Comparator(s) Comparator dosing and frequency

Adverse events from comparator

Length of treatment

Akcam 2006 [3]

30% glucose solution 1ml drop – frequency

unclear None

Placebo - distilled water

1ml drop - unclear how

often None

NR - at least 8 days

Alves 2012 [4]

Mentha piperita 1 drop per kg body

weight daily None Simethicone

Liquid drops - 2.5 mg per kg body weight

daily

None

7 days for each

treatment with a

washout period of 3

days in between

Arikan 2008 [5]

1) massage, 2) sucrose solution, 3) herbal tea and

4) hydrolysed formula

1) Parents were advised to administer massage twice a day

for 25 minutes duration during

symptoms of colic, 2) 2 ml of 12%

solution twice a day at 5 pm and 8 pm,

3) fennel tea was administered at a

dose of 35 ml (maximum dose of

150 ml) three times a day,

4) hydrolysed formula (dose not reported)

NR Control (no intervention)

NA NR 1 week

Aviner 2010 [31]

Gali-col Baby (homeopathic remedy)

The manufacturer’s recommended dose is “up to 5 drops which might be repeated

once in 15 minutes or

All 11 patients had an ALTE. 9/11 (81.8%) infants who

received Gali-col

NA NA NA NA

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according to the physician or pharmacist

instructions.” The amount of Gali-col Baby administered was recorded for 8

patients. For 3 patients, it was much

greater than the manufacturer’s

recommended dose, 4 other infants received the drug several times a day, and 1 patient

received a single recommended dose.

Baby showed at least 2

symptoms of an ALTE (this may be misleading because only

patients with an ALTE were

included in this study) Six

patients were hospitalised for 1 day, four were hospitalised for 2 days, and 1

was hospitalised for 3 day

Berseth 2009 [6]

Soy-based formula (Soy; Enfamil, ProSobee, LIPIL)

NA

41 (50% ) experienced at least 1 adverse

event

Partially hydrolysed cow's milk

protein, low-lactose formula

NA

44 (58%) experienced at least 1 adverse

event: (P = 0.34)

28 days

Bongers 2007 [7]

A new infant formula (NF; Nutrilon Omneo, Nutricia

Nederland BV, Zoetermeer, the Netherlands) which

contains modified vegetable oil with a high proportion

(41%) of palmitic acid at the sn-2 position, a mixture of prebiotic oligosaccharides, partially hydrolysed whey

protein and a reduced lactose content

NA No serious

adverse effects Standard formula

NA No serious

adverse effects

Two - 3 week treatment periods

Browning Spinal manipulative therapy Treatment was given None Occipito-sacral Treatment None 2 weeks

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Length of treatment

2008 [8] 2 -3 times per week, for 2 weeks, or less if

the symptoms resolved

decompression was given 2 - 3 times per week, for 2 weeks, or less if the symptoms resolved

Chau 2015 [9]

Probiotic L reuteri DSM 17938 (10

8 cfu)

5 drops orally, once daily

None

Placebo - the same excipient ingredients but without the live

bacteria

5 drops orally, once

daily None 21 days

Ciftci 2007 [32]

Treatments used by parents included: Taking the infant to a calm and dark room; holding the infant in their arms; rocking the infant;

positioning the infant; giving a massage to the infant;

warming the infant; having the infant listen to music;

giving the infant fennel tea; giving the infant anise;

giving the infant simethicone (metsil); taking the infant to

the hospital; giving the infant a sweet drink; giving the

infant lemon water; stimulating the rectum;

giving the infant olive oil; Using suppositories

NA NR NA NA NR NA

Cirgin 2006 [10]

Dr. Brown's Natural Flow baby bottle

NA NR Placebo baby

bottle NA NR 14 days


Probiotic L reuteri (DSM 17938) (10

8 cfu)

5 drops, once daily None Placebo Not explicitly

stated None 8 weeks

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Length of treatment

Dupont 2010 [12]

α-lactalbumin-enriched and probiotic-supplemented

infant formula (Lactobacillus rhamnosus, Bifidobacterium

infantis)

NA

44% experienced GI-

side effects; 15%

experienced feeding related

side effects (‘feeding-related’ GI side effects were: vomiting (one infant), colitis (one

infant)

Control formula (not enriched in α-lactalbumin, with a higher quantity of

proteins and lactose, and

neither probiotics nor

starch)

NA

67% experienced GI-side effects;

85% experienced feeding related

side effects ('feeding related’ GI side effects

were: constipation (five), vomiting (four), colitis

(one), regurgitations

(three) and flatulence (one

infant)

1 month

Hayden 2006 [13]

Cranial osteopathic manipulation

Once a week NR No treatment

Once a week (all infants

were brought to the

osteopathic clinic)

NR 4 weeks

Hill 2005 [14]

Low-allergen maternal elimination diet (mothers

excluded all foods containing dairy products, soy, wheat, eggs, peanuts,

tree nuts, and fish from their diet. Their diet included a

rice milk drink, meats, vegetables, fruits, and

cereals (corn and rice). A calcium supplement (1.2 g/day) was prescribed.

Mothers were supplied with a rice-based drink in powder form (500 mL/day), as well

NA NR

Control diet that included these foods (Mothers received 7 days of rations of a soy and cow’s milk powder

mixture to make 500 mL of a milk

drink per day (equivalent to 200 mL of soy

milk and 300 mL of cow’s milk). Mothers were

NA NR 1 week

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Length of treatment

as a daily supply of fresh rice bread)

asked to eat 1 serving of peanuts, 1 serving of

wheat, and 1 chocolate muesli

bar per day. Mothers were encouraged to maintain their usual intake of

vegetables, meats, rice, and other cereals)


A range of formulas belonging to the Novalac

line (Anti-Colic, Anti-Regurgitation, Anti-

Diarrhoea, Anti-Constipation)

NR

3.9% suffered an adverse event. Most

frequent affected the

digestive tract (1.4%), including

diarrhoea and constipation,

and respiratory (0.7%) (e.g. bronchitis,

bronchiolitis). Ten infants

(0.5%) required hospital

admission for septicaemia

(n=1), dehydration (n=2), hernia

(n=1) and

NR NR NR

Unclear – (patients

were included into

the study over a period

of two weeks. And

"patients were visited

on two occasions: at

the time of inclusion and

after four weeks"

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Length of treatment

bronchitis or bronchiolitis

(n=2)

Keefe 2006 [15]

"REST Routine for Infant Irritability" - an individualised

intervention programme 4 week programme NR

"Standard well-child care"

4 week programme

NR

4 weeks treatment over am 8 week study

period

Kianifar 2014 [16]

Protexom Restore; a mixture of seven probiotic

strains (Lactobacillus casei, L. rhamnosus, S.

thermophiles, Bifidobacterium breve, L.

acidophilus, B. infantis, L. bulgaricus) plus

fructooligosacharide

Parents advised to mix treatment or

placebo sachet with breast milk daily for a

period of 30 days

None

Placebo - matched for

size, volume, shape and

manufactured by the same company

Same as treatment - daily for 30

days

None 30 days

Landgren 2010 [2]

Acupuncture

Structured programme with six visits to the

clinic, including acupuncture

NR Control group

Structured programme

with six visits to the clinic,

without acupuncture

NR Six weeks

Mi 2015 [17]

L. reuteri DSM 17938 daily None Placebo daily None 28 days

Miller 2012 [34]

Chiropractic treatment Varied NR NA NA NA Varied

Moravej 2010 [18]

Mothers of infants in the case group were asked to avoid cow and goat milk as well as dairy products for 2 weeks and were prescribed calcium supplements, and

instructed to take a calcium-rich diet.

NA NR No change in

the mother's diet (regular diet)

NA NR 2 weeks

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Length of treatment

Oshikoya 2009 [35]

353 infants were treated using self-medication:

Herbal medicines (183/51.8%);

Nospamin (125/35.4%); Gripe water (106/30%); Bonababe (19/5.4%);

Piccan (7/2%); Kidcare (4/1.1%);

Teething powder (4/1.1%); Gbomoro (3/0.8%);

Paracetamol (3/0.8%); Ascorbic acid (3/0.8%);

Ampicillin/cloxacillin (3/0.8%)

120 (31.8%) used

chiropractic intervention (e.g. massage)

133 (35.2%) used

psychosocial interventions

157 mothers sought hospital-based intervention -

59.3% of infants were prescribed medicines

(Nospamin: 49.5%; Gripe water: 43%; Piccan: 12.9%;

Erythromycin: 10.8%; Abidec: 9.7%); 24.8% of

mothers received counselling

NA NA NA NA NA NA

Reinthal 2008 [19]

Children were breastfed prior to treatment. Light

needling (minimal

Light needling session every two weeks

NR Received same

procedure by the parents and

Every two weeks

NR 2 weeks (4 treatments

total)

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Length of treatment

acupuncture) by penetrating the skin with a 0.2mm sterile

disposable needle at acupuncture site LI4,

located between the thumb and forefinger, deep enough

to reach the dorsal interosseous muscle, on both left and right hands. The needle was briefly

rotated for a few seconds (less than 5), left in place for

another period of second and then removed

caring by the investigator

except for light needling

Salisbury 2012 [20]

Therapy sessions in which a behavioural paediatrician

and mental health clinician worked together to assess potential causes of infant

crying and to address emotional and psychological needs of parents. Clinicians

worked with patients to develop and individualised family treatment plan which

families took home

Therapy at baseline, 2- and 6-week follow

up NR

Standard care from own

healthcare provider

Standard care- clinic

appointments at times

individualised to families

NR 10 weeks

Savino 2015 [21]

L. reuteri DSM 17938 + vitamin D3

108 cfu + 400 UI NR vitamin D3 400 UI daily NR 12 weeks

Savino 2010 [22]

A suspension of freeze-dried lactobacillus reuteri in a mixture of sunflower oil

and medium-chain triglyceride oil supplied in a 5-mL dark bottle fitted with a

dropper cap.

5 drops, once a day, 30 minutes before the

feed in the morning

Rhinitis (n=1) (deemed

unrelated to study product).

Placebo - identical in

appearance and taste but without the live bacteria.

5 drops, once a day, 30 minutes

before the feed in the morning

Eczema (n=1), fever (n=1), otalgy

(n=1), gastroesophageal

reflux (n =1).

21 days

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Length of treatment

Savino 2006 [23]

New formula: formula contains partially hydrolysed whey proteins, a mixture of

OS 0.8 g/100 ml, comprising 90% galacto-OS and 10%

fructo OS low lactose level, modified vegetable oil with 41% of the palmitic acid in the b-position and starch.

The feeding volume was based on a

feeding ad libitum procedure. Feeding

frequency was decided by parents

NR Standard formula +

simethicone

simethicone (6 mg/kg

twice a day) NR 14 days

Savino 2007 [24]

Probiotic L reuteri (American Type Culture Collection strain 55730)

108 cfu in 5 drops of a commercially available oil

suspension, 30 minutes after feeding,

once per day

None simethicone

60 mg/day in 15 drops

twice per day of a

commercially available

solution, after feeding

None 28

days

Skjeie 2013 [25]

Acupuncture - The GP made a mark, 3 mm in

diameter, at the point ST36 bilaterally on all children, to hide the insertion mark. In the intervention group, an ethylene-oxidised sterile

Seirin acupuncture-needle (0.20 X15mm) was inserted

at the acupuncture point ST36. The point was needled bilaterally to

approximately 12 mm depth. The two needles were left

inserted without manipulation for 30

seconds. The needles were withdrawn and the insertion area was was covered with

The same procedure was performed on

days 4 and 5.

No serious adverse events

An identical procedure,

except for the needle

insertions

The same procedure

was performed on days 4 and 5.


5 days

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Length of treatment

an adhesive dressing.

Sung 2014 [26]

L reuteri DSM 17938 (0.2×10

8 cfu per drop) in an

oil suspension

Five drops orally given once daily

None

Maltodextrin in the same oil

suspension with the same

appearance, colour and taste as the treatment,

identically packaged and

stored.

NR None One month

Szajewska 2013 [27]

L reuteri DSM 17938, administered orally,

or placebo.

108 cfu. 5 drops, 1

time daily None

Identical formulation in all respects except

that the live probiotic

bacteria were excluded

5 drops, 1 time daily

None 21 days

Key: cfu – colony forming units; NR: Not reported; NA: Not Applicable; GP: General Practitioner

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Table 1.5: Cost of illness studies: details of evidence and results

Study ID Method of estimating COI Components

included Evidence sources

Currency and year

Results Limitations

Park 2015 [30]

Measurement of hospitalisations from the Kids Inpatient Sample Database

(KIDS) covering 44 US states with calculation of mean cost

per stay

Hospitalisations

Admissions database and

hospital charges

2009 US$

The rate of discharge for those under 12 months was 0.8 per 10,000 discharges for constipation, 1.0 per 10,000 discharges for

abdominal pain and 0.1 per 10,000 discharges for dyspepsia. Average cost per hospitalization

for FGID increased from $6115 (1997) to $18058 (2009); Costs for patients diagnosed with abdominal pain increased (on average)

from $3558 to $13331; Length of hospital stay increased from 1.7 (1997) to 2.0 (2009) days; Costs for IBS increased from $5278 (1997) to $18853 (2009); Costs for abdominal migraine

increased from $4876 (1997) to $15139 (2009); Costs for dyspepsia increased from $12674 to $35898 (2009); Costs for fecal incontinence

increased from $6609 to $13252 (2009); Costs for constipation increased from $3693 to

$11873. The costs for all hosptializations of paediatric FGIDs increased significantly from

1997 to 2009 .

Costs are for all children under 18

Sethi 2014 [29]

Measurement of inpatient stays from national inpatient

sample (NIS) database (approx 20% sample of USA

inpatient stays) with calculation of mean cost per

stay

Inpatient stays


hospital charges

2010 US$

Mean costs per stay were $17,518 in 2010 but this was for all patients (children and adults).

Total admissions for children under 12 months from the NIS database was 499 in 2010

Provides only a 20% sample and

costs are for children and

adults.

Sommers 2014 [28]

Measurement of ED visits from Nationwide Emergency

Department Sample (NEDS) database (approx 20% sample

of USA ED Visits) with calculation of mean cost per

visit

ED visits ED database and hospital

charges 2011 US$

Mean costs per ED visit were $2,470 in 2011 but this was for all patients (children and

adults). Total ED visits in 2011 from the NEDS database was 50,934 for children under 12

months



adults.

Key: COI – cost of ilness; ED – emergency department; FGID - Functional gastrointestinal disorders.

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1.5 RISK OF BIAS ASSESSMENT

The risk of bias (quality) of the 26 included RCTs was generally unclear (Table 1.6). Five

trials had a high risk of bias [13, 19-21, 24]; six trials had an unclear risk of bias [5, 6, 11, 12,

15, 18]; seven trials had a low/unclear risk of bias [2, 4, 8, 14, 16, 17, 25]; eight trials had a

low risk of bias [3, 7, 9, 10, 22, 23, 26, 27].

The quality of the 5 eligible observational studies was generally poor. Further details of the

quality assessment for the observational studies are reported in Table 1.7.

The quality of the cost of illness studies was generally good being based upon database

analysis and providing reasonable samples of the entire population. However, the studies

were focussed on just one aspect of the cost of illness and the costs applied were not

specific to infants under 12 months. The risk of bias assessment of the three COI studies is

reported in Table 1.8.

1.6 CONCLUSIONS

The systematic review identified a range of treatments that have been or are used for infant

FGID from countries across all continents. It also identified three studies from the USA that

estimated an aspect of the COI of FGID. However, the detail contained in all identified

studies was insufficient to generate a unified COI calculation for a single country. In

particular, there was no evidence found on the scale of use of different treatments and

interventions for infant FGID and colic outside of the use of hospital care in the USA,

predominantly for constipation.

The information identified in the systematic review, whilst not directly estimating a COI of

infant FGID in any particular country, provides useful background in constructing a de novo

calculation.

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Table 1.6: Systematic review: Risk of bias assessment of RCTs

Study ID

Was the allocation sequence

adequately generated?

Was allocation adequately concealed?

Was knowledge of the allocated interventions adequately prevented during the

study?

Were incomplete

outcome data adequately addressed?

Are reports of the study free of suggestion of selective

outcome reporting?

Was the study apparently free

of other problems that

could put it at a high risk of

bias?

Overall risk of bias

Akcam 2006 [3] Yes Yes Yes No Unclear Yes Low

Alves 2012 [4] Yes Unclear Yes Yes Unclear Unclear Low/Unclear

Arikan 2008 [5] Unclear Unclear No Yes Unclear Unclear Unclear

Berseth 2009 [6] Unclear Unclear Unclear Yes Unclear Yes Unclear

Bongers 2007 [7] Yes Yes Yes Unclear Unclear Unclear Low

Browning 2008 [8] Yes Unclear Yes No Unclear Unclear Low/Unclear

Chau 2015 [9] Yes Yes Yes No Unclear Yes Low

Cirgin 2006 [10] Yes Yes Yes No Unclear Yes Low

Coccorullo 2010 [11] Yes Unclear Unclear No Unclear Unclear Unclear

Dupont 2010 [12] Unclear Unclear Unclear No Unclear Yes Unclear

Hayden 2006 [13] Yes Unclear No No Unclear Unclear High

Hill 2005 [14] Yes Unclear Yes Yes Unclear Yes Low/Unclear

Keefe 2006 [15] Yes Unclear Unclear Yes Unclear Yes Unclear

Kianifar 2014 [16] Yes Unclear Yes Yes Yes Yes Low/Unclear

Landgren 2010 [2] Yes Unclear Yes Yes Yes Yes Low/Unclear

Mi 2015 [17] Yes Unclear Yes Yes Unclear Yes Low/Unclear

Moravej 2010 [18] Unclear Unclear Yes No Unclear Unclear Unclear

Reinthal 2008 [19] No Unclear Unclear NA Yes Yes High

Salisbury 2012 [20] Unclear Unclear No Unclear Yes No High

Savino 2015 [21] Yes No Unclear Yes Yes Yes High

Savino 2010 [22] Yes Yes Yes No Yes Yes Low

Savino 2006 [23] Yes Yes Yes No Unclear Yes Low

Savino 2007 [24] Yes No No No Yes Yes High

Skjeie 2013 [25] Unclear Yes Yes No Unclear Yes Low/Unclear

Sung 2014 [26] Yes Yes Yes No Yes Yes Low

Szajewska 2013 [27] Yes Yes Yes Yes Yes Yes Low

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Table 1.7: Systematic review: Risk of bias assessment of observational studies

Cohort study

Is there sufficient description of the groups and the distribution of prognostic factors?

Is the group(s) assembled at a similar point in their disease progression?

Is the intervention / treatment reliably ascertained?

Were the groups comparable on all important confounding factors?

Was there adequate adjustment for the effects of these confounding variables?

Was a dose-response relationship between intervention and outcome demonstrated?

Was outcome assessment blind to exposure status?

Was follow up long enough for the outcomes to occur?

What proportion of the cohort was followed up?

Were drop-out rates and reasons for drop-out similar across intervention and unexposed groups?

Miller 2012 [34] Yes No No No Yes Not Applicable No

Not Applicable

Not Applicable

No

Overall quality: Poor Precludes any association of changes seen with treatment as all the effects observed may be a consequence of effect upon the mothers reporting rather than direct effects on the infant. Subject to sampling bias, limited to one teaching clinic.

Case series

Is the study based on a representative sample selected from a relevant population?

Are the criteria for inclusion explicit?

Did all individuals enter the survey at a similar point in their disease progression?

Was follow-up long enough for important events to occur?

Were outcomes assessed using objective criteria or was blinding used?

If comparisons of sub-series are being made, was there sufficient description of the series and the distribution of prognostic factors?

Aviner 2010 [31] Yes Yes Yes NA (retrospective) Yes NA

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Cross sectional

Representativeness of the sample

Sample size: a) Justified satisfactory. * b) Not justified

Non-respondents:

Ascertainment of the exposure (risk factor)

Comparability: The subjects in different outcome groups are comparable based on the study design or analysis. Confounding factors are controlled.

Assessment of the outcom

Statistical test of the outcome.

Ciftci 2007 [32] Truly representative of the average in the

target population Satisfactory

No description of the characteristics of non-responders

Non-validated measurement tool, but the tool is available or

described

Only one group Self-report Statistical analysis

described


Non-random sample Not justified Only one group No description of measurement tool

Only one group Investigator assessed

Statistical analysis

described

Oshikoya 2009 [35]

Truly representative of the average in the

target population Not justified Only one group

No description of validation tool



described

Table 1.8: Systematic review: Quality assessment of COI studies

Study ID

Was the COI method clearly described?

Were the quality of the data used assessed and described?

Were data sources and dates clearly reported?

Were data gaps described?

Were data extrapolations reasonable?

Were reasonable methods employed to avoid double counting?

Were the calculations of cost clearly described?

Were the methods used to handle uncertainty appropriate?

Have the researchers offered assessments of the limitations of the study approach?


Park 2015[30] Yes No Yes No NA Unclear Unclear Unclear Yes Yes

Sethi 2014[29] Yes Yes Yes

Yes - only primary

diagnosis recorded Yes NR Yes

No uncertainty analysis

undertaken Yes Yes

Sommers 2015[28] Yes Yes Yes

Yes - only primary



undertaken Yes Yes

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16. Kianifar H, Ahanchian H, Grover Z, Jafari S, Noorbakhsh Z, Khakshour A, et al. Synbiotic

in the management of infantile colic: a randomised controlled trial. J Paediatr Child Health.

2014;50(10):801-5.

17. Mi G-L, Zhao L, Qiao D-D, Kang W-Q, Tang M-Q, Xu J-K. Effectiveness of Lactobacillus

reuteri in infantile colic and colicky induced maternal depression: a prospective single blind

randomized trial. Antonie van Leeuwenhoek. 2015;107(6):1547-53.

18. Moravej H, Imanieh MH, Kashef S, Handjani F, Eghterdari F. Predictive value of the

cow's milk skin prick test in infantile colic. Ann Saudi Med. 2010;30(6):468-70.

19. Reinthal M, Andersson S, Gustafsson M, Plos K, Lund I, Lundeberg T, et al. Effects of

minimal acupuncture in children with infantile colic - A prospective, quasi-randomised single

blind controlled trial. Acupunct Med. 2008;26(3):171-82.

20. Salisbury AL, High P, Twomey JE, Dickstein S, Chapman H, Liu J, et al. A randomized

control trial of integrated care for families managing infant colic. Infant Ment Health J.

2012;33(2):110-22.

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21. Savino F, Ceratto S, Poggi E, Cartosio ME, Cordero di Montezemolo L, Giannattasio A.

Preventive effects of oral probiotic on infantile colic: a prospective, randomised, blinded,

controlled trial using Lactobacillus reuteri DSM 17938. Benef Microbes. 2015;6(3):245-51.

22. Savino F, Cordisco L, Tarasco V, Palumeri E, Calabrese R, Oggero R, et al.

Lactobacillus reuteri DSM 17938 in infantile colic: a randomized, double-blind, placebo-

controlled trial. Pediatrics. 2010;126(3):e526-33.

23. Savino F, Palumeri E, Castagno E, Cresi F, Dalmasso P, Cavallo F, et al. Reduction of

crying episodes owing to infantile colic: A randomized controlled study on the efficacy of a

new infant formula. Eur J Clin Nutr. 2006;60(11):1304-10.

24. Savino F, Pelle E, Palumeri E, Oggero R, Miniero R. Lactobacillus reuteri (American

Type Culture Collection Strain 55730) versus simethicone in the treatment of infantile colic: a

prospective randomized study. Pediatrics. 2007;119(1):e124-30.

25. Skjeie H, Skonnord T, Fetveit A, Brekke M. Acupuncture for infantile colic: a blinding-

validated, randomized controlled multicentre trial in general practice. Scand J Prim Health

Care. 2013;31(4):190-6.

26. Sung V, Hiscock H, Tang MLK, Mensah FK, Nation ML, Satzke C, et al. Treating infant

colic with the probiotic Lactobacillus reuteri: double blind, placebo controlled randomised

trial. BMJ. 2014;348:g2107.

27. Szajewska H, Gyrczuk E, Horvath A. Lactobacillus reuteri DSM 17938 for the

management of infantile colic in breastfed infants: a randomized, double-blind, placebo-

controlled trial. J Pediatr. 2013;162(2):257-62.

28. Sommers T, Corban C, Sengupta N, Jones M, Cheng V, Bollom A, et al. Emergency

department burden of constipation in the United States from 2006 to 2011. Am J

Gastroenterol. 2015;110(4):572-9.

29. Sethi S, Mikami S, Leclair J, Park R, Jones M, Wadhwa V, et al. Inpatient burden of

constipation in the United States: an analysis of national trends in the United States from

1997 to 2010. Am J Gastroenterol. 2014;109(2):250-6.

30. Park R, Mikami S, LeClair J, Bollom A, Lembo C, Sethi S, et al. Inpatient burden of

childhood functional GI disorders in the USA: an analysis of national trends in the USA from

1997 to 2009. Neurogastroenterol Motil. 2015;27(5):684-92.

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31. Aviner S, Berkovitch M, Dalkian H, Braunstein R, Lomnicky Y, Schlesinger M. Use of a

homeopathic preparation for "infantile colic" and an apparent life-threatening event.

Pediatrics. 2010;125(2):e318-23.

32. Ciftci EK, Arikan D. Methods used to eliminate colic in infants in the eastern parts of

Turkey. Public Health Nurs. 2007;24(6):503-10.

33. Infante Pina D, Badia Llach X, Arino-Armengol B, Villegas Iglesias V. Prevalence and

dietetic management of mild gastrointestinal disorders in milk-fed infants. World J

Gastroenterol. 2008;14(2):248-54.

34. Miller J, Newell D. Prognostic significance of subgroup classification for infant patients

with crying disorders: A prospective cohort study. J Can Chiropr Assoc. 2012;56(1):40-8.

35. Oshikoya KA, Senbanjo IO, Njokanma OF. Self-medication for infants with colic in

Lagos, Nigeria. BMC Pediatr. 2009;9:9.

36. Wessel MA, Cobb JC, Jackson EB, Harris GS, Jr., Detwiler AC. Paroxysmal fussing in

infancy, sometimes called colic. Pediatrics. 1954;14(5):421-35.

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APPENDIX A

Search Strategies for the Systematic Review

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Appendix A i

A.1: Source: MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid

MEDLINE(R) 1946 to Present.

Interface: Ovid SP

Coverage: 1946 to present. Updated daily.

Search date: 14/01/16

Retrieved records: 2793

Search strategy:

Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid

MEDLINE(R) <1946 to Present>

Search Strategy:

--------------------------------------------------------------------------------

1 "cost of illness"/ (19777)

2 (costing adj3 (illness$ or disease$ or sickness$)).ti,ab,kf. (39)

3 (burden adj3 (illness$ or disease$ or sickness$)).ti,ab,kf. (18484)

4 (burden adj3 (family or families or human$1 or mother$ or father$ or parent$ or

caregiver$ or care-giver$)).ti,ab,kf. (5253)

5 ((economic or human$) adj3 consequence$1).ti,ab,kf. (4627)

6 "costs and cost analysis"/ or cost-benefit analysis/ (105504)

7 exp health care costs/ (50444)

8 (cost or costs or economic evaluation or pharmacoeconomic).ti,ab,kf. (367790)

9 (resource$1 adj4 use$1).ti,ab,kf. (20035)

10 (resource$1 adj4 usage).ti,ab,kf. (402)

11 (resource$1 adj4 utili$).ti,ab,kf. (10141)

12 (visit or visits or hospitalization$1 or hospitalisation$1 or admission$1 or admitted or

emergency room or rescue).ti,ab,kf. (495389)

13 quality-adjusted life years/ or "quality of life"/ (137895)

14 (quality adjusted life or qol).ti,ab,kf. (30636)

15 (qaly$ or qald$ or qale$ or qtime$).ti,ab,kf. (6312)

16 (sf36 or sf 36 or sf thirtysix or sf thirty six).ti,ab,kf. (15336)

17 (sf6 or sf 6 or short form or shortform or sf six or sfsix).ti,ab,kf. (21906)

18 (sf12 or sf 12 or sf twelve or sftwelve).ti,ab,kf. (2821)

19 (sf16 or sf 16 or sf sixteen or sfsixteen).ti,ab,kf. (19)

20 (sf20 or sf 20 or sf twenty or sftwenty).ti,ab,kf. (310)

21 (euroqol or eq5d or eq 5d).ti,ab,kf. (5304)

22 (hql or hqol or hrqol or hrql or hr ql).ti,ab,kf. (12031)

23 (hye or hyes).ti,ab,kf. (57)

24 health$1 year$1 equivalent$1.ti,ab,kf. (40)

25 (hui or hui1 or hui2 or hui3).ti,ab,kf. (1051)

26 disutili$.ti,ab,kf. (273)

27 (quality adj3 (wellbeing or well being)).ti,ab,kf. (1606)

28 qwb.ti,ab,kf. (185)

29 (willingness adj3 pay).ti,ab,kf. (2954)

30 standard gamble$.ti,ab,kf. (712)

31 (time trade off$1 or time tradeoff$1 or tto or timetradeoff).ti,ab,kf. (1349)

32 ((valu$ or measur$) adj3 (health or outcome$1 or effect$1 or change$1 or

state$1)).ti,ab,kf. (305820)

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33 (preference$ adj3 (patient$1 or public or valu$ or measur$)).ti,ab,kf. (13395)

34 ((quality adj3 life) or qol).ti,ab,kf. (180949)

35 (index adj3 wellbeing).ti,ab,kf. (90)

36 (multiattribute$ health or multi attribute$ health).ti,ab,kf. (54)

37 (multiattribute$ theor$ or multi attribute$ theor$ or multiattribute$ analys$ or multi

attribute$ analys$).ti,ab,kf. (10)

38 (multiattribute$ utilit$ or multi attribute$ utilit$).ti,ab,kf. (214)

39 (utilit$ adj3 (valu$ or measur$ or health or life or estimat$ or elicit$ or disease)).ti,ab,kf.

(7231)

40 (euro qual or euroqual).ti,ab,kf. (15)

41 (visual analog$ or vas).ti,ab,kf. (52444)

42 (prom or proms or patient reported outcome$1 or pro or pros).ti,ab,kf. (139404)

43 functional assessment.ti,ab,kf. (6663)

44 (symptom$1 adj4 (score$1 or scale$ or instrument$1 or measur$)).ti,ab,kf. (42712)

45 exp patient satisfaction/ (67136)

46 (satisfaction or dissatisf$ or unsatisf$).ti,ab,kf. (115925)

47 (anxiety or depression or anxious or depressed).ti,ab,kf. (373073)

48 exp emotions/ (184194)

49 exp fatigue/ or absenteeism/ or presenteeism/ (30147)

50 stress,psychological/ (93810)

51 (gastrointestinal rating scale or GSRS or (gastrointestinal quality adj3 index) or GIQLI

or (severity adj2 dyspepsia assessment) or SODA).ti,ab,kf. (3661)

52 ((parent$ or family or families or mother$ or father$ or caregiver$ or care-giver$) adj5

(concern$1 or perception$1 or view$1 or worry or worrie$1)).ti,ab,kf. or exp parents/px

(48279)

53 or/1-52 (2181547)

54 (colic/ or exp diarrhea/ or colonic diseases, functional/ or exp abdominal pain/) and

(exp infant/ or child, preschool/) (18890)

55 diarrhea, infantile/ (6791)

56 gastrointestinal diseases/ and pain/ and (exp infant/ or child, preschool/) (52)

57 (constipation/ or vomiting/) and (exp infant/ or child, preschool/) (5457)

58 ((infantile or infant$1 or baby or babies or neonat$ or newborn$1 or new born or

toddler$1 or child or children or pediatric or paediatric) adj5 (colic or constipation or

constipated or regurgitat$ or spitting or spit)).ti,ab,kf. (2580)


toddler$1 or child or children or pediatric or paediatric) adj5 (colicky or defecat$ or stool$1 or

bowel movement$1)).ti,ab,kf. (2979)

60 ((fgid or fgids) and (infantile or infant$1 or neonat$ or baby or babies or newborn$1 or

new born or toddler$1 or child or children or pediatric or paediatric)).ti,ab,kf. (111)

61 (crying adj5 (infantile or infant$1 or neonat$ or baby or babies or newborn$1 or new

born or toddler$1 or child or children or pediatric or paediatric)).ti,ab,kf. (1101)

62 (gastrointestinal adj5 (infantile or infant$1 or neonat$ or baby or babies or newborn$1

or new born or toddler$1 or child or children or pediatric or paediatric)).ti,ab,kf. (4306)

63 ((dyschezia or colonic inertia or diarrhea or diarrhoea or cramp$ or reflux or functional

abdominal pain or bowel symptom$1 or irritable bowel or IBS) adj5 (infantile or infant$1 or

neonat$ or baby or babies or newborn$1 or new born or toddler$1 or child or children or

pediatric or paediatric)).ti,ab,kf. (15466)

64 or/54-63 (39733)

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65 53 and 64 (6472)

66 exp animals/ not humans/ (4171020)

67 (news or comment or editorial or letter or case reports).pt. or case report.ti. (3216568)

68 65 not (66 or 67) (5990)

69 limit 68 to (english language and yr="2005 -Current") (2812)

70 remove duplicates from 69 (2793)

A.2: Source: Embase

Interface: Ovid SP

Coverage: 1974-13/01/2016



Search strategy:

Database: Embase <1974 to 2016 January 13>

Search Strategy:

--------------------------------------------------------------------------------


2 (costing adj3 (illness$ or disease$ or sickness$)).ti,ab,kw. (60)

3 (burden adj3 (illness$ or disease$ or sickness$)).ti,ab,kw. (27543)


caregiver$ or care-giver$)).ti,ab,kw. (7788)

5 ((economic or human$) adj3 consequence$1).ti,ab,kw. (5927)

6 exp "health care cost"/ (227557)

7 "cost benefit analysis"/ (70174)

8 (cost or costs or economic evaluation or pharmacoeconomic).ti,ab,kw. (492815)

9 (resource$1 adj4 use$1).ti,ab,kw. (27684)

10 (resource$1 adj4 usage).ti,ab,kw. (600)

11 (resource$1 adj4 utili$).ti,ab,kw. (16726)


emergency room or rescue).ti,ab,kw. (759153)

13 quality-adjusted life year/ or "quality of life"/ or gastrointestinal quality of life index/

(316485)

14 (quality adjusted life or qol).ti,ab,kw. (53815)

15 (qaly$ or qald$ or qale$ or qtime$).ti,ab,kw. (11705)

16 (sf36 or sf 36 or sf thirtysix or sf thirty six).ti,ab,kw. (24797)

17 (sf6 or sf 6 or short form or shortform or sf six or sfsix).ti,ab,kw. (28593)

18 (sf12 or sf 12 or sf twelve or sftwelve).ti,ab,kw. (4810)

19 (sf16 or sf 16 or sf sixteen or sfsixteen).ti,ab,kw. (35)

20 (sf20 or sf 20 or sf twenty or sftwenty).ti,ab,kw. (298)

21 (euroqol or eq5d or eq 5d).ti,ab,kw. (9656)

22 (hql or hqol or hrqol or hrql or hr ql).ti,ab,kw. (18786)

23 (hye or hyes).ti,ab,kw. (102)

24 health$1 year$1 equivalent$1.ti,ab,kw. (42)

25 (hui or hui1 or hui2 or hui3).ti,ab,kw. (1520)

26 disutili$.ti,ab,kw. (500)

27 (quality adj3 (wellbeing or well being)).ti,ab,kw. (2241)

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28 qwb.ti,ab,kw. (218)

29 (willingness adj3 pay).ti,ab,kw. (4665)

30 standard gamble$.ti,ab,kw. (887)

31 (time trade off$1 or time tradeoff$1 or tto or timetradeoff).ti,ab,kw. (1892)


state$1)).ti,ab,kw. (381531)

33 (preference$ adj3 (patient$1 or public or valu$ or measur$)).ti,ab,kw. (19215)

34 ((quality adj3 life) or qol).ti,ab,kw. (283686)

35 (index adj3 wellbeing).ti,ab,kw. (137)

36 (multiattribute$ health or multi attribute$ health).ti,ab,kw. (67)


attribute$ analys$).ti,ab,kw. (19)

38 (multiattribute$ utilit$ or multi attribute$ utilit$).ti,ab,kw. (277)

39 (utilit$ adj3 (valu$ or measur$ or health or life or estimat$ or elicit$ or

disease)).ti,ab,kw. (11011)

40 (euro qual or euroqual).ti,ab,kw. (24)

41 (visual analog$ or vas).ti,ab,kw. (76768)

42 (prom or proms or patient reported outcome$1 or pro or pros).ti,ab,kw. (203085)

43 functional assessment.ti,ab,kw. (10049)

44 (symptom$1 adj4 (score$1 or scale$ or instrument$1 or measur$)).ti,ab,kw. (64027)

45 patient preference/ or patient satisfaction/ (105494)

46 (satisfaction or dissatisf$ or unsatisf$).ti,ab,kw. (157169)

47 (anxiety or depression or anxious or depressed).ti,ab,kw. (505966)

48 exp emotion/ (420006)

49 fatigue/ or exhaustion/ or lassitude/ (138163)

50 absenteeism/ or job performance/ or productivity/ (54173)

51 caregiver burden/ or emotional stress/ or mental stress/ or maternal stress/ or parental

stress/ (84316)


or (severity adj2 dyspepsia assessment) or SODA).ti,ab,kw. (4773)


(concern$1 or perception$1 or view$1 or worry or worrie$1)).ti,ab,kw. (21366)

54 or/1-53 (3222665)

55 infantile colic/ or newborn vomiting/ or infantile diarrhea/ (3950)

56 (colic/ or diarrhea/ or chronic diarrhea/ or colon disease/ or intestine function disorder/

or exp abdominal pain/ or irritable colon/ or defecation disorder/) and (exp infant/ or

preschool child/) (22242)

57 (gastrointestinal pain/ or gastrointestinal symptom/) and (exp infant/ or preschool child/)

(2097)

58 (exp constipation/ or vomiting/) and (exp infant/ or preschool child/) (14916)



constipated or regurgitat$ or spitting or spit)).ti,ab,kw. (3546)



bowel movement$1)).ti,ab,kw. (3761)


new born or toddler$1 or child or children or pediatric or paediatric)).ti,ab,kw. (222)

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born or toddler$1 or child or children or pediatric or paediatric)).ti,ab,kw. (1426)


or new born or toddler$1 or child or children or pediatric or paediatric)).ti,ab,kw. (5608)




pediatric or paediatric)).ti,ab,kw. (17369)

65 or/55-64 (58135)

66 54 and 65 (11408)

67 (editorial or letter or note).pt. (2039212)

68 case report/ or case report.ti. (2087284)

69 (animal/ or animal experiment/ or animal model/ or animal tissue/ or nonhuman/) not

exp human/ (5260862)

70 66 not (67 or 68 or 69) (9940)


A.3: Source: PubMed

Interface: http://www.ncbi.nlm.nih.gov/pubmed/

Coverage: 1946-current. Updated daily



Search strategy:

Note – PubMed muddles the lines in the search history, and therefore the order of the

search lines is altered from the original MEDLINE strategy and is not especially logical.

#87 Search (#83 NOT #84) Filters: Publication date from 2005/01/01 to 2016/12/31;

English 1395

#86 Search (#83 NOT #84) Filters: Publication date from 2005/01/01 to 2016/12/31

1442

#85 Search (#83 NOT #84) 1569

#84 Search MEDLINE[sb] 22893753

#83 Search (#80 NOT (#81 OR #82)) 15594

#82 Search animals[mh] NOT humans[mh:noexp] 4167646

#81 Search news[pt] OR editorial[pt] OR letter[pt] OR comment[pt] OR case reports[pt]

OR case report[ti] 3223352

#80 Search (#79 AND #62) 17287

#79 Search (#63 OR #64 OR #65 OR #66 OR #67 OR #68 OR #69 OR #70 OR #71 OR

#72 OR #73 OR #74 OR #75 OR #76 OR #77 OR #78) 70185

#78 Search (infantile[ot] OR infant[ot] OR infants[ot] OR baby[ot] OR babies[ot] OR

neonat*[ot] OR newborn*[ot] OR new born[ot] OR toddler*[ot] OR child[ot] OR children[ot]

OR pediatric[ot] OR paediatric[ot]) AND (dyschezia[ot] OR colonic inertia[ot] OR diarrhea[ot]

OR diarrhea[ot] OR cramp*[ot] OR reflux[ot] OR functional abdominal pain[ot] OR bowel

symptom*[ot] OR irritable bowel[ot] OR IBS[ot]) 2364

#77 Search (infantile[tiab] OR infant[tiab] OR infants[tiab] OR baby[tiab] OR babies[tiab]

OR neonat*[tiab] OR newborn*[tiab] OR new born[tiab] OR toddler*[tiab] OR child[tiab] OR

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children[tiab] OR pediatric[tiab] OR paediatric[tiab]) AND (dyschezia[tiab] OR colonic

inertia[tiab] OR diarrhea[tiab] OR diarrhea[tiab] OR cramp*[tiab] OR reflux[tiab] OR

functional abdominal pain[tiab] OR bowel symptom*[tiab] OR irritable bowel[tiab] OR

IBS[tiab]) 26271



OR pediatric[ot] OR paediatric[ot]) AND gastrointestinal[ot] 807



children[tiab] OR pediatric[tiab] OR paediatric[tiab]) AND gastrointestinal[tiab] 17631



OR pediatric[ot] OR paediatric[ot]) AND crying[ot] 59



children[tiab] OR pediatric[tiab] OR paediatric[tiab]) AND crying[tiab] 2477



OR pediatric[ot] OR paediatric[ot]) AND (fgid[ot] OR fgids[ot]) 2



children[tiab] OR pediatric[tiab] OR paediatric[tiab]) AND (fgid[tiab] OR fgids[tiab]) 115



OR pediatric[ot] OR paediatric[ot]) AND (colicky[ot] OR defecat*[ot] OR stool*[ot] OR bowel

movement*[ot]) 53



children[tiab] OR pediatric[tiab] OR paediatric[tiab]) AND (colicky[tiab] OR defecat*[tiab] OR

stool*[tiab] OR bowel movement*[tiab]) 11169



OR pediatric[ot] OR paediatric[ot]) AND (colic[ot] OR constipation[ot] OR constipated[ot] OR

regurgitat*[ot] OR spitting[ot] OR spit[ot]) 244



children[tiab] OR pediatric[tiab] OR paediatric[tiab]) AND (colic[tiab] OR constipation[tiab]

OR constipated[tiab] OR regurgitat*[tiab] OR spitting[tiab] OR spit[tiab]) 7520

#66 Search (Constipation[mh:noexp] OR vomiting[mh:noexp]) AND (infant[mh] OR child,

preschool[mh:noexp]) 5459

#65 Search gastrointestinal diseases[mh:noexp] AND pain[mh:noexp] AND (infant[mh]

OR child, preschool[mh:noexp]) 52

#64 Search diarrhea, infantile[mh:noexp] 6788

#63 Search (colic[mh:noexp] OR diarrhea[mh] OR colonic diseases, functional[mh:noexp]

OR abdominal pain[mh]) AND (infant[mh] OR child, preschool[mh:noexp]) 18868

#62 Search (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11

OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22


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OR #56 OR #57 OR #58 OR #59 OR #60 OR #61) 3966477

#61 Search euroqual[tiab] OR euro qual[tiab] OR euroqual[ot] OR euro qual[ot] 16

#60 Search ((parent*[tiab] OR family[tiab] OR families[tiab] OR mother*[tiab] OR

father*[tiab] OR caregiver*[tiab] OR care-giver*[tiab]) AND (concern*[tiab] OR

perception*[tiab] OR view*[tiab] OR worry[tiab] OR worrie*[tiab])) OR

"Parents/psychology"[Mesh] 97038

#59 Search (parent*[ot] OR family[ot] OR families[ot] OR mother*[ot] OR father*[ot] OR

caregiver*[ot] OR care-giver*[ot]) AND (concern*[ot] OR perception*[ot] OR view*[ot] OR

worry[ot] OR worrie*[ot]) 522

#58 Search symptom*[ot] AND (score*[ot] OR scale*[ot] OR instrument*[ot] OR

measur*[ot]) 746

#57 Search satisfaction[tiab] OR dissatisf*[tiab] OR unsatisf*[tiab] OR satisfaction[ot] OR

dissatisf*[ot] OR unsatisf*[ot] 119170

#56 Search anxiety[tiab] OR depression[tiab] OR anxious[tiab] OR depressed[tiab] OR

anxiety[ot] OR depression[ot] OR anxious[ot] OR depressed[ot] 381561

#55 Search emotions[mh] 184091

#54 Search stress,psychological[mh] 99836

#53 Search fatigue[mh] OR absenteeism[mh:noexp] OR presenteeism[mh:noexp]

30106

#52 Search (gastrointestinal[tiab] AND rating scale[tiab]) OR (gastrointestinal[ot] AND

rating scale[ot]) 603

#51 Search GSRS[tiab] OR GIQLI[tiab] OR SODA[tiab] OR GSRS[ot] OR GIQLI[ot] OR

SODA[ot] 3609

#50 Search gastrointestinal[tiab] AND quality[tiab] AND index[tiab] 834

#49 Search severity[tiab] AND dyspepsia[tiab] AND assessment[tiab] 118

#48 Search utilit*[tiab] AND (valu*[tiab] OR measur*[tiab] OR health[tiab] OR life[tiab] OR

estimat*[tiab] OR elicit*[tiab] OR disease[tiab]) 78309

#47 Search utilit*[ot] AND (valu*[ot] OR measur*[ot] OR health[ot] OR life[ot] OR

estimat*[ot] OR elicit*[ot] OR disease[ot]) 289

#46 Search visual analog*[tiab] OR vas[tiab] OR visual analog*[ot] OR vas[ot] 53203

#45 Search prom[ot] OR proms[ot] OR patient reported outcome*[ot] OR pro[ot] OR

pros[ot] OR prom[tiab] OR proms[tiab] OR patient reported outcome*[tiab] OR pro[tiab] OR

pros[tiab] 143056

#44 Search functional assessment[tiab] OR functional assessment[ot] 6822

#43 Search symptom*[tiab] AND (score*[tiab] OR scale*[tiab] OR instrument*[tiab] OR

measur*[tiab]) 238078

#42 Search patient satisfaction[mh] 67067

#41 Search (valu*[tiab] OR measur*[tiab]) AND (health[tiab] OR outcome*[tiab] OR

effect*[tiab] OR change*[tiab] OR state*[tiab]) 2131060

#40 Search (valu*[ot] OR measur*[ot]) AND (health[ot] OR outcome*[ot] OR effect*[ot] OR

change*[ot] OR state*[ot]) 7042

#39 Search preference*[tiab] AND (patient[tiab] OR patients[tiab] OR public[tiab] OR

valu*[tiab] OR measur*[tiab]) 47688

#38 Search preference*[ot] AND (patient[ot] OR patients[ot] OR public[ot] OR valu*[ot]

OR measur*[ot]) 814

#37 Search (quality[tiab] AND life[tiab]) OR qol[tiab] 204509

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#36 Search (quality[ot] AND life[ot]) OR qol[ot] 9470

#35 Search (index[tiab] AND wellbeing[tiab]) OR (index[ot] AND wellbeing[ot]) 503

#34 Search multiattribute*[tiab] OR multi attribute*[tiab] OR multiattribute*[ot] OR multi

attribute*[ot] 603

#33 Search healthy years equivalent[tiab] OR healthy years equivalent[ot] 23

#32 Search hui[tiab] OR hui1[tiab] OR hui2[tiab] OR hui3[tiab] OR hui[ot] OR hui1[ot] OR

hui2[ot] OR hui3[ot] 1064

#31 Search disutili*[tiab] OR disutili*[ot] 282

#30 Search quality[tiab] AND (wellbeing[tiab] OR well being[tiab]) 14021

#29 Search quality[ot] AND (wellbeing[ot] OR well being[ot]) 157

#28 Search qwb[tiab] OR qwb[ot] 186

#27 Search (willingness[ot] AND pay[ot]) OR (willingness[tiab] AND pay[tiab]) 3312

#26 Search standard gamble[tiab] OR standard gamble[ot] 715

#25 Search time trade off*[ot] OR time tradeoff*[ot] OR tto[ot] OR timetradeoff[ot] OR time

trade off*[tiab] OR time tradeoff*[tiab] OR tto[tiab] OR timetradeoff[tiab] 1385

#24 Search visit[tiab] OR visits[tiab] OR hospitalization*[tiab] OR hospitalisation*[tiab] OR

admission*[tiab] OR admitted[tiab] OR emergency room[tiab] OR rescue[tiab] 505212

#23 Search visit[ot] OR visits[ot] OR hospitalization*[ot] OR hospitalisation*[ot] OR

admission*[ot] OR admitted[ot] OR emergency room[ot] OR rescue[ot] 3817

#22 Search quality-adjusted life years[mh:noexp] or quality of life[mh:noexp] 137823

#21 Search quality adjusted life[tiab] OR qol[tiab] OR quality adjusted life[ot] OR qol[ot]

31622

#20 Search qaly*[tiab] OR qald*[tiab] OR qale*[tiab] OR qtime*[tiab] OR qaly*[ot] OR

qald*[ot] OR qale*[ot] OR qtime*[ot] 6516

#19 Search sf36[ot] OR sf 36[ot] OR sf36[tiab] or sf 36[tiab] 15719

#18 Search sf6[tiab] OR sf 6[tiab] OR short form[tiab] OR shortform[tiab] OR sf six[tiab]

OR sfsix[tiab] 22568

#17 Search hye[tiab] OR hyes[tiab] OR hye[ot] OR hyes[ot] 57

#16 Search hql[tiab] OR hqol[tiab] OR hrqol[tiab] OR hrql[tiab] OR hr ql[tiab] OR hql[ot]

OR hqol[ot] OR hrqol[ot] OR hrql[ot] OR hr ql[ot] 12433

#15 Search euroqol[tiab] OR eq5d[tiab] OR eq 5d[tiab] OR euroqol[ot] OR eq5d[ot] OR eq

5d[ot] 5548

#14 Search sf16[tiab] OR sfsixteen[tiab] OR sf16[ot] OR sfsixteen[ot] OR sf20[tiab] OR

sftwenty[tiab] OR sf20[ot] OR sftwenty[ot] 31

#13 Search sf12[tiab] OR sftwelve[tiab] OR sf12[ot] OR sftwelve[ot] 217

#12 Search sf6[ot] OR sf 6[ot] OR short form[ot] OR shortform[ot] OR sf six[ot] OR

sfsix[ot] 242

#11 Search resource use[tiab] OR resource usage[tiab] OR resource utili*[tiab] OR

resource use[ot] OR resource usage[ot] OR resource utili*[ot] 11538

#10 Search cost[ot] OR costs[ot] OR economic evaluation[ot] OR pharmacoeconomic[ot]

7838

#9 Search cost[tiab] OR costs[tiab] OR economic evaluation[tiab] OR

pharmacoeconomic[tiab] 377282

#8 Search "costs and cost analysis"[mh:noexp] OR cost-benefit analysis[mh:noexp] OR

health care costs[mh] 142701

#7 Search (economic[ot] OR human*[ot]) AND consequence*[ot] 14

#6 Search (economic[tiab] OR human*[tiab]) AND consequence*[tiab] 52990

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#5 Search burden[ot] AND (family[ot] OR families[ot] OR human*[ot] OR mother*[ot] OR

father*[ot] OR parent*[ot] OR caregiver*[ot] OR care-giver*[ot]) 441

#4 Search burden[tiab] AND (family[tiab] OR families[tiab] OR human*[tiab] OR

mother*[tiab] OR father*[tiab] OR parent*[tiab] OR caregiver*[tiab] OR care-giver*[tiab])

27962

#3 Search (costing[ot] OR burden[ot]) AND (illness*[ot] OR disease*[ot] OR

sickness*[ot]) 596

#2 Search (costing[tiab] OR burden[tiab]) AND (illness*[tiab] OR disease*[tiab] OR

sickness*[tiab]) 53782

#1 Search cost of illness[mh:noexp] 19779

A.4: Source: PsycINFO

Interface: Ovid SP

Coverage: 1806-January Week 2 2016



Search strategy:

1 exp "costs and cost analysis"/ (21310)

2 Health Care Economics/ or Pharmacoeconomics/ (810)

3 (costing adj3 (illness$ or disease$ or sickness$)).ti,ab,id. (5)

4 (burden adj3 (illness$ or disease$ or sickness$)).ti,ab,id. (3340)


caregiver$ or care-giver$)).ti,ab,id. (4180)

6 ((economic or human$) adj3 consequence$1).ti,ab,id. (1447)

7 (cost or costs or economic evaluation or pharmacoeconomic).ti,ab,id. (72698)

8 (resource$1 adj4 use$1).ti,ab,id. (7968)

9 (resource$1 adj4 usage).ti,ab,id. (152)

10 (resource$1 adj4 utili$).ti,ab,id. (2629)


emergency room or rescue).ti,ab,id. (95253)

12 "quality of life"/ (30977)

13 (quality adjusted life or qol).ti,ab,id. (7917)

14 (qaly$ or qald$ or qale$ or qtime$).ti,ab,id. (803)

15 (sf36 or sf 36 or sf thirtysix or sf thirty six).ti,ab,id. (3552)

16 (sf6 or sf 6 or short form or shortform or sf six or sfsix).ti,ab,id. (9357)

17 (sf12 or sf 12 or sf twelve or sftwelve).ti,ab,id. (809)

18 (sf16 or sf 16 or sf sixteen or sfsixteen).ti,ab,id. (0)

19 (sf20 or sf 20 or sf twenty or sftwenty).ti,ab,id. (42)

20 (euroqol or eq5d or eq 5d).ti,ab,id. (1292)

21 (hql or hqol or hrqol or hrql or hr ql).ti,ab,id. (3836)

22 (hye or hyes).ti,ab,id. (13)

23 health$1 year$1 equivalent$1.ti,ab,id. (5)

24 (hui or hui1 or hui2 or hui3).ti,ab,id. (438)

25 disutili$.ti,ab,id. (158)

26 (quality adj3 (wellbeing or well being)).ti,ab,id. (1293)

27 qwb.ti,ab,id. (91)

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28 (willingness adj3 pay).ti,ab,id. (1320)

29 standard gamble$.ti,ab,id. (188)

30 (time trade off$1 or time tradeoff$1 or tto or timetradeoff).ti,ab,id. (311)


state$1)).ti,ab,id. (77177)

32 (preference$ adj3 (patient$1 or public or valu$ or measur$)).ti,ab,id. (6173)

33 ((quality adj3 life) or qol).ti,ab,id. (51129)

34 (index adj3 wellbeing).ti,ab,id. (114)

35 (multiattribute$ health or multi attribute$ health).ti,ab,id. (14)


attribute$ analys$).ti,ab,id. (17)

37 (multiattribute$ utilit$ or multi attribute$ utilit$).ti,ab,id. (235)

38 (utilit$ adj3 (valu$ or measur$ or health or life or estimat$ or elicit$ or disease)).ti,ab,id.

(3270)

39 (euro qual or euroqual).ti,ab,id. (4)

40 (visual analog$ or vas).ti,ab,id. (6171)

41 (prom or proms or patient reported outcome$1 or pro or pros).ti,ab,id. (14435)

42 functional assessment.ti,ab,id. (2267)

43 (symptom$1 adj4 (score$1 or scale$ or instrument$1 or measur$)).ti,ab,id. (20641)

44 (satisfaction or dissatisf$ or unsatisf$).ti,ab,id. (98236)

45 (anxiety or depression or anxious or depressed).ti,ab,id. (313389)

46 exp Emotions/ (253774)

47 fatigue/ (7014)

48 employee absenteeism/ (1964)

49 exp job performance/ (17969)

50 psychological stress/ (7972)


or (severity adj2 dyspepsia assessment) or SODA).ti,ab,id. (656)


(concern$1 or perception$1 or view$1 or worry or worrie$1)).ti,ab,id. (27094)

53 Caregiver Burden/ (4856)

54 or/1-53 (862938)

55 infant vocalization/ (992)


toddler$1 or child or children or pediatric or paediatric).id. or (pediatrics/ or exp infant

development/)) and (colon disorders/ or gastrointestinal disorders/ or constipation/ or

diarrhea/ or irritable bowel syndRome/ or crying/) (1008)


toddler$1 or child or children or pediatric or paediatric) and (colic or constipation or

constipated or regurgitat$ or spitting or spit)).ti,ab,id. (540)


toddler$1 or child or children or pediatric or paediatric) and (colicky or defecat$ or stool$1 or

bowel movement$1)).ti,ab,id. (322)


new born or toddler$1 or child or children or pediatric or paediatric)).ti,ab,id. (16)

60 (crying and (infantile or infant$1 or neonat$ or baby or babies or newborn$1 or new

born or toddler$1 or child or children or pediatric or paediatric)).ti,ab,id. (1789)

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61 (gastrointestinal and (infantile or infant$1 or neonat$ or baby or babies or newborn$1

or new born or toddler$1 or child or children or pediatric or paediatric)).ti,ab,id. (664)


abdominal pain or bowel symptom$1 or irritable bowel or IBS) and (infantile or infant$1 or


pediatric or paediatric)).ti,ab,id. (749)

63 or/55-62 (4627)

64 54 and 63 (1338)



A.5: Source: NHS Economic Evaluation Database (NHS EED)

Interface: Cochrane Library – Wiley

Coverage: Issue 2 of 4 April 2015

Search date: 17/01/16 and 03/02/16

Retrieved records: 25 (22 and 3)

Search Name:

Date Run: 17/01/16 18:13:19.750

Description:

ID Search Hits

#1 [mh ^colic] or [mh diarrhea] or [mh ^"colonic diseases, functional"] or [mh "abdominal

pain"] or [mh ^constipation] or [mh ^vomiting] 7012

#2 [mh infant] or [mh ^"child, preschool"] 13527

#3 #1 and #2 238

#4 [mh ^"diarrhea, infantile"] 454

#5 [mh ^"gastrointestinal diseases"] and [mh ^pain] 53

#6 #5 and #2 0

#7 (infantile or infant? or baby or babies or neonat* or newborn? or "new born" or

toddler? or child or children or pediatric or paediatric) near/5 (colic or constipation or

constipated or regurgitat* or spitting or spit) 491


toddler? or child or children or pediatric or paediatric) near/5 (colicky or defecat* or stool? or

bowel next movement?) 198

#9 (FGID or FGIDS) and (infantile or infant? or baby or babies or neonat* or newborn?

or "new born" or toddler? or child or children or pediatric or paediatric) 13


toddler? or child or children or pediatric or paediatric) near/5 crying 268


toddler? or child or children or pediatric or paediatric) near/5 gastrointestinal 443

#12 (dyschezia or "colonic inertia" or diarrhea or diarrhoea or cramp? or reflux or

"functional abdominal pain" or bowel next symptom? or "irritable bowel" or IBS) near/5

(infantile or infant? or baby or babies or neonat* or newborn? or "new born" or toddler? or

child or children or pediatric or paediatric) 2014

#13 #12 or #11 or #10 or #9 or #8 or #7 or #6 or #5 or #4 or #3 3163

#14 #13 Publication Year from 2005 to 2016, in Economic Evaluations 22

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#15 #13 Publication Year from 2005 to 2016, in Technology Assessments 10

#16 #13 Publication Year from 2005 to 2016, in Other Reviews 94

Search rerun 03/02/16 after it was noted that the ? wildcard was not performing correctly in

Cochrane interface. Searched again using the * truncation option in place of the ? –

combined with the original search results using NOT to find only “new” records

ID Search Hits




#3 #1 and #2 258



#6 #5 and #2 0

















#13 #12 or #11 or #10 or #9 or #8 or #7 or #6 or #4 or #3 3231




#16 #14 and #15 258



#19 #17 and #18 0

#20 (infantile or infant* or baby or babies or neonat* or newborn* or new next born* or

toddler* or child or children or pediatric or paediatric) near/5 (colic or constipation or



toddler* or child or children or pediatric or paediatric) near/5 (colicky or defecat* or stool* or

bowel next movement*) 384

#22 (FGID or FGIDS) and (infantile or infant* or baby or babies or neonat* or newborn* or

new next born* or toddler* or child or children or pediatric or paediatric) 14

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toddler* or child or children or pediatric or paediatric) near/5 crying 412


toddler* or child or children or pediatric or paediatric) near/5 gastrointestinal 628

#25 (dyschezia or "colonic inertia" or diarrhea or diarrhoea or cramp* or reflux or

"functional abdominal pain" or bowel next symptom* or "irritable bowel" or IBS) near/5

(infantile or infant* or baby or babies or neonat* or newborn* or new next born* or toddler* or





#29 #28 not #27 3

A.6: Source: Health Technology Assessment Database (HTA Database)


Coverage: Issue 4 of 4 October 2015

Search date: 17/01/16 and 03/02/16


Search strategy:

Search Name:

Date Run: 17/01/16 18:13:19.750

Description:

ID Search Hits




#3 #1 and #2 238



#6 #5 and #2 0















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ID Search Hits




#3 #1 and #2 258



#6 #5 and #2 0





















#16 #14 and #15 258



#19 #17 and #18 0




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#29 #28 not #27 1

A.7: Source: Database of Abstracts of Reviews of Effects (DARE)



Search date: 17/01/16 and 03/03/16


Search strategy:

ID Search Hits




#3 #1 and #2 238



#6 #5 and #2 0















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ID Search Hits




#3 #1 and #2 258



#6 #5 and #2 0





















#16 #14 and #15 258



#19 #17 and #18 0




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#29 #28 not #27 15

A.8: Source: NEXIS UK

Interface: LexisNexis

Coverage: No information provided. Last update 19/01/16



Search strategy:

Search of this database intended to identify commercial/market reports on over the counter

sales of interventions

All searches had the following limits applied: Search Market Insight, 01/01/2005 – 20/01/16.

Search All Countries, All Industries, All 20 sources.

Each search string searched separately and the full text downloaded as a Word document.

(infantile OR infant* OR baby OR babies OR neonat? OR newborn* OR “new born” OR

toddler* OR child OR children OR pediatric OR paediatric) W/5 (colic OR constipation OR

constipated OR regurgitat? OR spitting OR spit) 62 results


toddler* OR child OR children OR pediatric OR paediatric) W/5 (colicky OR defecat? OR

stool* OR “bowel movement*”) 42 results


toddler* OR child OR children OR pediatric OR paediatric) and (fgid or fgids) 0 results


toddler* OR child OR children OR pediatric OR paediatric) W/5 (crying OR cry). Due to the

excessive volume of irrelevant results returned by this search line, these terms were

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additionally limited to the following industries: Food, Health Care, Marketing & Advertising,

Pharmaceuticals, Retail & Wholesale Trade. 27 results.


toddler* OR child OR children OR pediatric OR paediatric) W/5 gastrointestinal 146 results


toddler* OR child OR children OR pediatric OR paediatric) W/5 (dyschezia OR “colonic

inertia” OR diarrhea OR diarrhoea OR cramp? OR reflux OR “functional abdominal pain” OR

“bowel symptom*” OR “irritable bowel” OR IBS) Due to the excessive volume of irrelevant

results returned by this search line, these terms were additionally limited to the following

industries: Food, Health Care, Marketing & Advertising, Pharmaceuticals, Retail &

Wholesale Trade. 251 results.

A.9: Source: CEA Registry

Interface:https://research.tufts-

nemc.org/cear4/SearchingtheCEARegistry/SearchtheCEARegistry.aspx

Coverage: No information provided.



Search strategy:

Database only supports searching single terms – following used 1 at a time

No export options available. Information specialist added potentially relevant records ONLY

to EndNote by hand. Duplicate records not added.

Colic 3 records/0 potentially relevant

Colicky 0 records

Constipation 5 records/0 potentially relevant

Constipated 1 record/0 potentially relevant

Regurgitation 5 records/0 potentially relevant

Regurgitate 0 records

Regurgitates 0 records

Spitting 0 records

Spits 0 records [NB spit could not be used as a search term as it retrieved over 900 records,

all of the first 5 pages were irrelevant suggesting it is overly sensitive]

Defecation 0 records

Defecate 0 records

Defecated 0 records

Stool 3 records/0 potentially relevant

Stooling 0 records

Stools 0 records

Bowel 29 records/0 potentially relevant

IBS 14 records/0 potentially relevant

FGID 0 records

FGIDS 0 records

Cry 11 records/0 potentially relevant

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Crying 0 records

Gastrointestinal 65 records/0 potentially relevant

Dyschezia 0 records

Colon 78 records/0 potentially relevant

Colonic 11 records/0 potentially relevant

Diarrhea 9 records/0 potentially relevant


Cramp 2 records/ 0 potentially relevant

Cramps 0 records

Cramping 0 records

Reflux 27 records/0 potentially relevant

A.10: Source: NHS Evidence Search

Interface: http://www.evidence.nhs.uk/




Search strategy:

Note: NHS Evidence is not intended for systematic or structured searches and it does not

have the functionality to support this. The search was translated pragmatically in order to

allow it to be used in NHS Evidence, prioritizing the most specific search terms.

(infantile OR infant* OR baby OR babies OR neonat* OR newborn* OR "new born*" OR

toddler* OR child OR children OR pediatric OR paediatric) AND (fgid or fgids or "functional

gastrointestinal disorder*") 22 records.

(infantile OR infant* OR baby OR babies OR neonat* OR newborn* OR “new born*” OR

toddler* OR child OR children OR pediatric OR paediatric) AND (colic OR colicky) In order to

manage the search volumes the results were filtered by publication type: primary research,

systematic reviews, ongoing research and health technology assessment. 120 records.


toddler* OR child OR children OR pediatric OR paediatric) AND (“excessive crying” OR

“inconsolable crying”) In order to manage the search volumes the results were filtered by

publication type: primary research, systematic reviews, ongoing research and health

technology assessment. 16 records.

(infantile OR infant* OR baby OR babies OR neonat* OR newborn* OR new born* OR

toddler* OR child OR children OR pediatric OR paediatric) AND (regurgitat* OR spit OR

spitting) In order to manage the search volumes the results were filtered by publication type:

primary research, systematic reviews, ongoing research and health technology assessment.

147 records.

All records rapidly assessed by information specialist – 38 potentially relevant records cut

and pasted into Word document. 16 of these had not been previously identified by other

search resources and so were added to EndNote.

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A.11: Source: REPEC

Interface: IDEAS https://ideas.repec.org




Search strategy:

Each search line run individually

(infantile | infant* | baby | babies | neonat* | newborn* | "new born" | “new borns” | toddler* |

child | children | pediatric | paediatric) + (colic | colicky) 1 record


child | children | pediatric | paediatric) + (regurgitat* | spit | spitting) 0 records

fgid | fgids 0 records


child | children | pediatric | paediatric) + (cry OR crying) 24 records


child | children | pediatric | paediatric) + (constipation | constipated) 4 records


child | children | pediatric | paediatric) + (defecat* | stool* | “bowel movement” | "bowel

movements" | gastrointestinal) 22 records


child | children | pediatric | paediatric) + (dyschezia | “colonic inertia” | diarrhea | diarrhoea |

cramp* | reflux | “functional abdominal pain”) 129 records


child | children | pediatric | paediatric) + ("bowel symptom" | "bowel symptoms" | IBS |

"irritable bowel") 1 record

All results rapidly assessed in REPEC by the information specialist for relevance. Only

records not previously identified by database searches were added to EndNote. 1

potentially relevant, non duplicate record remained after this process.

A.12: Source: OAISTER

Interface: Worldcat http://oaister.worldcat.org/



Retrieved records:240

Search strategy:

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Note: OAISTER is not intended for systematic or structured searches and it does not have

the functionality to support this. The search was translated pragmatically in order to allow it

to be used in this resource, prioritizing the most specific search terms.

Each search line run individually and the following limits applied: Non juvenile, English

language only, 2005-2016

'kw:(infantile OR infant* OR baby OR babies OR neonat* OR newborn* OR “new born” OR

“new borns” OR toddler* OR child OR children OR pediatric OR paediatric) AND (colic OR

colicky)' 104 records

‘kw(infantile OR infant* OR baby OR babies OR neonat* OR newborn* OR “new born” OR

“new borns” OR toddler* OR child OR children OR pediatric OR paediatric) AND (fgid or

fgids or "functional gastrointestinal disorder" OR “functional gastrointestinal disorders”)’ 47

records


“new borns” OR toddler* OR child OR children OR pediatric OR paediatric) AND

(inconsolab* OR excessiv*) AND (cry OR crying)’ 21 records


“new borns” OR toddler* OR child OR children OR pediatric OR paediatric) AND (regurgitat*

OR spit OR spitting) 68

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A.13: Source: International Society For Pharmacoeconomics and Outcomes

Research (ISPOR ) conference



Search strategy:

Latin America Conference (every 2 years) – 2013 and 2015 – both indexed in Embase – no

handsearching required

Annual European Congress – 2013, 2014, 2015 – all three indexed in Embase – no


Annual International Meeting – 2013, 2014, 2015 - all three indexed in Embase – no


Asia Pacific Conference (every 2 years) – 2014 – not indexed – handsearched

ISPOR 6TH Asia-Pacific Conference 6-9 September 2014. Beijing, China. Abstract book

scanned by eye by an information specialist at

http://www.ispor.org/conferences/beijing0914/ISPOR-6th-Asia-Pacific-Conference-

Research-Abstracts.pdf [Accessed 18th December 2015]. 0 potentially relevant records

identified.

The ISPOR Scientific Presentation Database

[https://www.ispor.org/RESEARCH_STUDY_DIGEST/research_index.asp] was also

browsed on 18/12/13 for presentations catagorised as the disease group:

a) GI Disorders (8 results returned - no potentially relevant records identified);

b) Health – Children (10 results returned - no potentially relevant records identified);

c) Multiple Diseases. (125 results returned – no potentially relevant records identified)

A.14: Source: European Society for Paediatric Gastroenterology, Hepatology and

Nutrition (ESPGHAN) conference



Search strategy:

2013, 2014, 2015 annual meeting abstracts not indexed in Embase and so were

handsearched.

As the terms for the population that must be used to search the abstracts using the “Control

F” function (such as FGID, constipation, diarrhoea) are too imprecise in the context of this

confernece to be used efficeintly, and the list of necessary search terms to capture the costs

concept was prohibitively long, it was decided to scan the abstract book by eye to identify

any potentially relevant studies. The decision to select an abstract was made by the

information specialist – to minimise the risk of missing potentially relevant studies, selection

was over inclusive if there was any doubt on the relevance of the abstract.

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ESPGHAN Annual Meeting May 6-9 2015; Amsterdam Abstract book searched online at

http://espghan.org/uploads/media/ESPGHAN_A4_Abstract_2015_v2.pdf

[Accessed 3rd February 2016].

5 abstracts selected

ESPGHAN Annual Meeting June 9-12 2014; Jerusalem Abstract book searched online at

http://journals.lww.com/jpgn/Documents/ESPGHAN%202014%20Abstracts%20-

%20Complete%20abstracts.pdf



ESPGHAN Annual Meeting May 8-11 2013; London Abstract book searched online at

http://journals.lww.com/jpgn/Documents/ESPGHAN%20Abstracts%202013.pdf



A.15: Source: North American Society for Pediatric Gastroenterology, Hepatology

and Nutrition (NASPGHAN) conference



Search strategy:


handsearched.








NASPGHAN Annual Meeting October 8-11 2015; Washington, DC. Abstract book

searched online at

http://journals.lww.com/jpgn/Documents/Abstracts%20from%202015%20NASPGHAN%20M

eeting%20in%20Washington,%20DC.pdf [Accessed 18th December 2015].

1 abstract selected

NASPGHAN Annual Meeting October 23-26 2014; Atlanta, GA. Abstract book searched

online at http://journals.lww.com/jpgn/Documents/NASPGHAN%202014%20abstracts.pdf

[Accessed 18th December 2015].

1 abstract selected

NASPGHAN Annual Meeting October 10-12 2013; Chicago, IL. Abstract book searched

online at http://journals.lww.com/jpgn/Documents/NASPGHAN2013_Abstract_Book%20-

%20revised%20Sept%2018,%202013.pdf Accessed 18th December 2015].

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http://journals.lww.com/jpgn/Documents/Abstracts%20from%202015%20NASPGHAN%20Meeting%20in%20Washington,%20DC.pdf

http://journals.lww.com/jpgn/Documents/ESPGHAN%202014%20Abstracts%20-%20Complete%20abstracts.pdf





http://journals.lww.com/jpgn/Documents/NASPGHAN%202014%20abstracts.pdf

http://journals.lww.com/jpgn/Documents/NASPGHAN2013_Abstract_Book%20-%20revised%20Sept%2018,%202013.pdf





A.16: Source: World Congress of Pediatric Gastroenterology, Hepatology and

Nutrition.



Search strategy:

Last conference held 2012, next in October 2016 so outside scope of search. Not

handsearched.

A.17: Source: American Academy of Pediatrics National Conference



Search strategy:

AAP National Conference October 24-27 2015; Washington, DC. Abstracts searchable

online at: https://aap.confex.com/aap/2015/webprogrampress/start.html

Accessed 3rd February 2015

Online database of abstracts –

Boolean search does not seem to be performing correctly – all search terms used one at a

time:

colic

colicky

cry

cries

crying

constipation

constipated

constipating

reflux

GERD

GORD

regurgitation

gastrointestinal

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gastro-intestinal

fgid

fgids

0 potentially relevant abstracts identified.

AAP National Conference October 11-14 2014; San Diego. Abstracts searchable online

at: https://aap.confex.com/aap/2014/webprogrampress/start.html Accessed 3rd February

2015



time:

colic

colicky

cry

cries

crying

constipation

constipated

constipating

reflux

GERD

GORD

regurgitation

regurgitate

gastrointestinal

gastro-intestinal

fgid

fgids

1 potentially relevant abstract identified

AAP National Conference October 26-29 2013; Orlando Abstracts searchable online at:

https://aap.confex.com/aap/2013/webprogram/start.html Accessed 3rd February 2015


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https://aap.confex.com/aap/2013/webprogram/start.html




time:

colic

colicky

cry

cries

crying

constipation

constipated

constipating

reflux

GERD

GORD

regurgitation

regurgitate

gastrointestinal

gastro-intestinal

fgid

fgids


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APPENDIX B

Excluded Studies

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Table B.1: Unobtainable records (1) Record Exclusion reason

Tikochinski Y, Kukliansky I. Examination of the effect of BornFree ActiveFlow baby bottles on infant colic. Gastroenterol Nurs. 2013;36(2):123-7.

Record unobtainable

Table B.2: Excluded records (125) with reasons for exclusion

Record Exclusion reason

Ansari H, Ansari Z, Hutson JM, Southwell BR. Potentially avoidable hospitalisation for constipation in Victoria, Australia in 2010-11. BMC Gastroenterol. 2014;14:125.

Ineligible patient population

Ansari H, Ansari Z, Lim T, Hutson JM, Southwell BR. Factors relating to hospitalisation and economic burden of paediatric constipation in the state of Victoria, Australia, 2002-2009. J Paediatr Child Health. 2014;50(12):993-9.


Arumugam J, Sivandam S, Vijayalakshmi AM. The evaluation and management of an incessantly crying infant. SLJCH. 2012;41(4):192-98.

Literature review

Asipu D, Jaffray B. Treatment of severe childhood constipation with restorative proctocolectomy. Arch Dis Child. 2010;95(11):867-70.


Bae SH, Son JS, Lee R. Effect of fluid intake on the outcome of constipation in children: PEG 4000 versus lactulose. Pediatr Int. 2010;52(4):594-7.


Barr RG, Rajabali F, Aragon M, Colbourne M, Brant R. Education about crying in normal infants is associated with a reduction in pediatric emergency room visits for crying complaints. J Dev Behav Pediatr. 2015;36(4):252-7.


Bishop J, Furman M, Thomson M. Omeprazole for gastroesophageal reflux disease in the first 2 years of life: a dose-finding study with dual-channel pH monitoring. J Pediatr Gastroenterol Nutr. 2007;45(1):50-5.

Ineligible population (babies

with gastroesophageal

reflux)

Bu LN, Chang MH, Ni YH, Chen HL, Cheng CC. Lactobacillus casei rhamnosus Lcr35 in children with chronic constipation. Pediatr Int. 2007;49(4):485-90.


Burgers R, Bonanno E, Madarena E, Graziano F, Pensabene L, Gardner W, et al. The care of constipated children in primary care in different countries. Acta Paediatr. 2012;101(6):677-80.

Ineligible study design

Calado CS, Pereira AG, Santos VN, Castro MJ, Maio JF. What brings newborns to the emergency department?: a 1-year study. Pediatr Emerg Care. 2009;25(4):244-8.

Prevalence study

Chao HC, Vandenplas Y. Effect of cereal-thickened formula and upright positioning on regurgitation, gastric emptying, and weight gain in infants with regurgitation. Nutrition. 2007;23(1):23-8.



reflux)

Chellani H, Dabas A, Arya S. Gastro-esophageal reflux: spitting and possetting in a neonate. Indian J Pediatr. 2015;82(1):39-43.

Literature review

Chen SL, Cai SR, Deng L, Zhang XH, Luo TD, Peng JJ, et al. Efficacy and complications of polyethylene glycols for treatment of constipation in children: a meta-analysis (Provisional abstract). DARE. 2014; (2): e65. Available from: http://onlinelibrary.wiley.com/o/cochrane/cldare/articles/DARE-12014063218/frame.html

Literature review

Chitkara DK, Talley NJ, Weaver AL, Katusic SK, De Schepper H, Rucker MJ, et al. Incidence of presentation of common functional gastrointestinal disorders in children from birth to 5 years: a cohort study. Clin Gastroenterol Hepatol. 2007;5(2):186-91.

Prevalence study

Chu H, Zhong L, Li H, Zhang X, Zhang J, Hou X. Epidemiology characteristics of constipation for general population, pediatric population, and elderly

Literature review

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population in china. Gastroenterol Res Pract. 2014;2014:532734.

Chumpitazi CE, Henkel EB, Valdez KL, Chumpitazi BP. Soap Suds Enema are Efficacious and Safe for Treating Fecal Impaction in Children with Abdominal Pain. J Pediatr Gastroenterol Nutr. 2015


Coccorullo P, Quitadamo P, Martinelli M, Staiano A. Novel and alternative therapies for childhood constipation. J Pediatr Gastroenterol Nutr. 2009;48(SUPPL. 2):S104-S06.

Literature review

Cohen Engler A, Hadash A, Shehadeh N, Pillar G. Breastfeeding may improve nocturnal sleep and reduce infantile colic: potential role of breast milk melatonin. Eur J Pediatr. 2012;171(4):729-32.


Collaco JM, Aherrera AD, Au Yeung KJ, Lefton-Greif MA, Hoch J, Skinner ML. Interdisciplinary pediatric aerodigestive care and reduction in health care costs and burden. JAMA Otolaryngol Head Neck Surg. 2015;141(2):101-5.


Cook F, Bayer J, Le HND, Mensah F, Cann W, Hiscock H. Baby Business: a randomised controlled trial of a universal parenting program that aims to prevent early infant sleep and cry problems and associated parental depression. BMC Pediatr. 2012;12:13.


Crotteau CA, Wright ST. What is the best treatment for infants with colic? J Fam Pract. 2006;55(7):634-36.

Literature review

Dattoli E, Tandoi F, Agosti M, Luini C, Meneghin F, Dilillo D, et al. Functional gastrointestinal disorders in infants and neonatal period: Which correlation? [Conference Abstract]. Dig Liver Dis. 2012;44:S264.

Conference abstract

Dehghani SM, Askarian M, Kaffashan HA. Oral domperidone has no additional effect on chronic functional constipation in children: a randomized clinical trial. Indian J Gastroenterol. 2014;33(2):125-30.


Dehghani SM, Erjaee A, Imanieh MH, Haghighat M. Efficacy of the standard quadruple therapy versus triple therapies containing proton pump inhibitor plus amoxicillin and clarithromycin or amoxicillin-clavulanic acid and metronidazole for helicobacter pylori eradication in children. Dig Dis Sci. 2009;54(8):1720-24.


Del Buono R, Wenzl TG, Ball G, Keady S, Thomson M. Effect of Gaviscon Infant on gastro-oesophageal reflux in infants assessed by combined intraluminal impedance/pH. Arch Dis Child. 2005;90(5):460-3.



reflux)

Devitt P, Thornley E, Hinks M. An evaluation of an inter-disciplinary constipation clinic for childhood constipation. J Res Nurs. 2007;12(5):539-47.


Di Mauro A, Riezzo G, Civardi E, Intini C, Corvaglia L, Ballardini E, et al. Act and not react: Prophylactic use of probiotic in colic, regurgitation and functional constipation, clinical and socio-economic impact. Dig Liver Dis. 2013;45:e302.

Conference abstract

Diamanti A, Bracci F, Reale A, Crisogianni M, Pisani M, Castro M. Incidence, clinical presentation, and management of constipation in a pediatric ED. Am J Emerg Med. 2010;28(2):189-94.

Prevalence study

Ditty A, Garg A, Leggett C, Turner S. Are proton pump inhibitors over-prescribed in infants? J Pharm Pract Res. 2014;44(4):220-23.



reflux)

Dupont C, Leluyer B, Maamri N, Morali A, Joye J-P, Fiorini J-M, et al. Double-blind randomized evaluation of clinical and biological tolerance of polyethylene glycol 4000 versus lactulose in constipated children. J Pediatr Gastroenterol Nutr. 2005;41(5):625-33.


Dziechciarz P, Horvath A, Szajewska H. Polyethylene glycol 4000 for treatment of functional constipation in children. J Pediatr Gastroenterol Nutr. 2015;60(1):65-8.


Elitsur Y. The diagnostic yield of upper endoscopy procedures in children- is it cost effective? Curr Gastroenterol Rep. 2014;16(5):385.


European School of Osteopathy. Cranial Osteopathy in Infantile Colic. In: UK Clinical Trials Gateway [internet]. 2013. Available from https://ukctg.nihr.ac.uk/trials/trial-details/trial-details?trialNumber=NCT01942928. Identifier: NCT01942928


Falconer J. Gastro-oesophageal reflux and gastrooesophageal reflux disease in infants and children. J Fam Health Care. 2010;20(5):175-7; quiz 78.


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Fazil M. Prevalence and risk factors for infantile colic in District Mansehra. J Ayub Med Coll Abbottabad. 2011;23(2):115-7.

Prevalence study

Gomes PB, Duarte MA, Melo Mdo C. Comparison of the effectiveness of polyethylene glycol 4000 without electrolytes and magnesium hydroxide in the treatment of chronic functional constipation in children. J Pediatr. 2011;87(1):24-8.


Hays LJ. Impact upon emotional availability: Infant GERD and infant massage therapy. Diss Abstr Int (B). 2015;75(9-B(E)):No Pagination Specified.


Hegar B, Rantos R, Firmansyah A, De Schepper J, Vandenplas Y. Natural evolution of infantile regurgitation versus the efficacy of thickened formula. J Pediatr Gastroenterol Nutr. 2008;47(1):26-30.



reflux)

Howard CR, Lanphear N, Lanphear BP, Eberly S, Lawrence RA. Parental responses to infant crying and colic: the effect on breastfeeding duration. Breastfeed Med. 2006;1(3):146-55.

Ineligible outcomes

Hua S, Peters RL, Allen KJ, Dharmage SC, Tang ML, Wake M, et al. Medical intervention in parent-reported infant gastro-oesophageal reflux: A population-based study. J Paediatr Child Health. 2014(Nov 11):[Epub ahead of print].


Hussain M, Batool F, Masood-Us-Syed SS. Association of various factors with infantile colic. Pak Paed J. 2013;37(4):217-21.

Ineligible outcomes

Hussain S, Kierkus J, Hu P, Hoffman D, Lekich R, Sloan S, et al. Safety and efficacy of delayed release rabeprazole in 1- to 11-month-old infants with symptomatic GERD. J Pediatr Gastroenterol Nutr. 2014;58(2):226-36.



reflux)

Iacono G, Merolla R, D'Amico D, Bonci E, Cavataio F, Di Prima L, et al. Gastrointestinal symptoms in infancy: a population-based prospective study. Dig Liver Dis. 2005;37(6):432-8.

Prevalence study

Iacovou M, Ralston RA, Muir J, Walker KZ, Truby H. Dietary management of infantile colic: a systematic review. Matern Child Health J. 2012;16(6):1319-31.

Literature review

Indrio F, Di Mauro A, Riezzo G, Cavallo L, Francavilla R. Infantile colic, regurgitation, and constipation: an early traumatic insult in the development of functional gastrointestinal disorders in children? Eur J Pediatr. 2015;174(6):841-2.


Indrio F, Di Mauro A, Riezzo G, Civardi E, Intini C, Corvaglia L, et al. Prophylactic use of a probiotic in the prevention of colic, regurgitation, and functional constipation: a randomized clinical trial. JAMA Pediatr. 2014;168(3):228-33.



reflux)

Indrio F, Di Mauro A, Riezzo G, Panza R, Cavallo L, Francavilla R. Prevention of functional gastrointestinal disorders in neonates: Clinical and socioeconomic impact. Benef Microbes. 2015;6(2):195-98.

Literature review

Indrio F, Riezzo G, Raimondi F, Bisceglia M, Cavallo L, Francavilla R. The effects of probiotics on feeding tolerance, bowel habits, and gastrointestinal motility in preterm newborns. J Pediatr. 2008;152(6):801-6.


Indrio F, Riezzo G, Raimondi F, Cavallo L, Francavilla R. Regurgitation in healthy and non healthy infants. Ital J Pediatr. 2009;35(1):39.

Literature review

Indrio F. Randomised controlled trial: Study concludes L. reuteri not effective for infant colic, but findings may be limited by participants' heterogeneity. Evid Based Med. 2014;19(6):215.


Jadcherla SR, Slaughter JL, Stenger MR, Klebanoff M, Kelleher K, Gardner W. Practice Variance, Prevalence, and Economic Burden of Premature Infants Diagnosed With GERD. Hosp Pediatr. 2013;3(4):335-41.


Johnson JD, Cocker K, Chang E. Infantile Colic: Recognition and Treatment. Am Fam Physician. 2015;92(7):577-82.

Literature review

Jordan B, Heine RG, Meehan M, Catto-Smith AG, Lubitz L. Effect of antireflux medication, placebo and infant mental health intervention on persistent crying: a randomized clinical trial. J Paediatr Child Health. 2006;42(1-2):49-58.



reflux)

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Jordan GJ. Elimination communication as colic therapy. Med Hypotheses. 2014;83(3):282-5.


Khan ZA, Ahmad S, Sheikh MY. Gastro esophageal reflux: an over investigated entity in neonates and infants. JPMA J Pak Med Assoc. 2010;60(12):984-6.



reflux)

Khoshoo V, Dhume P. Clinical response to 2 dosing regimens of lansoprazole in infants with gastroesophageal reflux. J Pediatr Gastroenterol Nutr. 2008;46(3):352-4.



reflux)

Kirby CN, Segal AY, Hinds R, Jones KM, Piterman L. Infant gastro-oesophageal reflux disease (GORD): Australian GP attitudes and practices. J Paediatr Child Health. 2016;52(1):47-53.


Koivusalo AI, Pakarinen MP, Wikstrom A, Rintala RJ. Assessment and treatment of gastroesophageal reflux in healthy infants with apneic episodes: a retrospective analysis of 87 consecutive patients. Clin Pediatr. 2011;50(12):1096-102.



reflux)

Kokke FT, Scholtens PA, Alles MS, Decates TS, Fiselier TJ, Tolboom JJ, et al. A dietary fiber mixture versus lactulose in the treatment of childhood constipation: a double-blind randomized controlled trial. J Pediatr Gastroenterol Nutr. 2008;47(5):592-7.


Koppen IJN, Lammers LA, Benninga MA, Tabbers MM. Management of Functional Constipation in Children: Therapy in Practice. Paediatr Drugs. 2015;17(5):349-60.


Korterink JJ, Ockeloen L, Benninga MA, Tabbers MM, Hilbink M, Deckers-Kocken JM. Probiotics for childhood functional gastrointestinal disorders: a systematic review and meta-analysis. Acta Paediatr. 2014;103(4):365-72.

Literature review

Kramer EA, den Hertog-Kuijl JH, van den Broek LM, van Leengoed E, Bulk AM, Kneepkens CM, et al. Defecation patterns in infants: a prospective cohort study. Arch Dis Child. 2015;100(6):533-6.

Ineligible study design: prevalence

study

Kuizenga-Wessel S, Benninga MA, Tabbers MM. Reporting outcome measures of functional constipation in children from 0 to 4 years of age. J Pediatr Gastroenterol Nutr. 2015;60(4):446-56.

Literature review

Kurowski J, Kaur S, Katsogridakis Y, Wershil BK, Bass LM. Educational Module Improves Emergency Department Evaluation for Suspected Constipation. J Pediatr. 2015;167(3):706-10.e1.


Landgren K, Hallstrom I. Parents' experience of living with a baby with infantile colic--a phenomenological hermeneutic study. Scand J Caring Sci. 2011;25(2):317-24.

Ineligible outcomes

Landgren K. Acupuncture in Practice: Investigating Acupuncturists' Approach to Treating Infantile Colic. Evid Based Complement Alternat Med. 2013. :Article ID 456712.

Ineligible outcomes

Landgren K, Tiberg I, Hallstrom I. Standardized minimal acupuncture, individualized acupuncture, and no acupuncture for infantile colic: study protocol for a multicenter randomized controlled trial - ACU-COL. BMC Altern Med. 2015;15:325.


Levitt MA, Pena A. Minimally invasive treatment of fecal incontinence and constipation in children. Minerva Chir. 2010;65(2):223-34.


Liem O, Harman J, Benninga M, Kelleher K, Mousa H, Di Lorenzo C. Health utilization and cost impact of childhood constipation in the United States. J Pediatr. 2009;154(2):258-62.


Litmanovitz I, Bar-Yoseph F, Lifshitz Y, Davidson K, Eliakim A, Regev RH, et al. Reduced crying in term infants fed high beta-palmitate formula: a double-blind randomized clinical trial. BMC Pediatr. 2014;14:152.


Loening-Baucke V, Pashankar DS. A randomized, prospective, comparison study of polyethylene glycol 3350 without electrolytes and milk of magnesia for children with constipation and fecal incontinence. Pediatrics. 2006;118(2):528-35.


Loots C, Kritas S, van Wijk M, McCall L, Peeters L, Lewindon P, et al. Body Ineligible

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positioning and medical therapy for infantile gastroesophageal reflux symptoms. J Pediatr Gastroenterol Nutr. 2014;59(2):237-43.

population (babies with

gastroesophageal reflux)

Martigne L, Delaage PH, Thomas-Delecourt F, Bonnelye G, Barthelemy P, Gottrand F. Prevalence and management of gastroesophageal reflux disease in children and adolescents: a nationwide cross-sectional observational study. Eur J Pediatr. 2012;171(12):1767-73.

Paediatric population

Maxted AE, Dickstein S, Miller-Loncar C, High P, Spritz B, Liu J, et al. Infant colic and maternal depression. Infant Ment Health J. 2005;26(1):56-68.

Ineligible outcomes

Miller J. Cry babies: A framework for chiropractic care. Clin Chiropr. 2007;10(3):139-46.


Miller J, Caprini Croci S. Cry baby, why baby? Beyond colic: Is it time to widen our views? J Clin Chiropr Pediatr. 2005;6:419-23.

Literature review

Miller JE. Costs of Routine Care for Infant Colic in the UK and Costs of Chiropractic Manual Therapy as a Management Strategy Alongside a RCT for this Condition. J Clin Chiropr Pediatr. 2013;14(1):1063-69.


Miyazawa R, Tomomasa T, Kaneko H, Arakawa H, Morikawa A. Effect of formula thickened with reduced concentration of locust bean gum on gastroesophageal reflux. Acta Paediatr. 2007;96(6):910-4.



reflux)

Mugie SM, Di Lorenzo C, Benninga MA. Constipation in childhood. Nat Rev Gastroenterol Hepatol. 2011;8(9):502-11.

Literature review

Mugie SM, Korczowski B, Bodi P, Green A, Kerstens R, Ausma J, et al. Prucalopride is no more effective than placebo for children with functional constipation. Gastroenterology. 2014;147(6):1285-95.e1.


Nel ED. Gastro-oesophageal reflux in infants and children. S Afr Fam Pract. 2013;54(5):414-17.

Literature review

Neu M, Schmiege SJ, Pan Z, Fehringer K, Workman R, Marcheggianni-Howard C, et al. Interactions during feeding with mothers and their infants with symptoms of gastroesophageal reflux. J Altern Complement Med. 2014;20(6):493-9.

Ineligible outcomes

Ngoenmak T, Treepongkaruna S, Buddharaksa Y, Khositseth A. Effects of Domperidone on QT Interval in Children with Gastroesophageal Reflux Disease. Pediatr neonatol. 2016;57(1):60-4.



reflux)

Noviello C, Romano M, Zangari A, Papparella A, Martino A, Cobellis G. Management of severe constipation in children. Minerva Pediatr. 2013;65(2):193-8.


Omari T, Davidson G, Bondarov P, Naucler E, Nilsson C, Lundborg P. Pharmacokinetics and acid-suppressive effects of esomeprazole in infants 1-24 months old with symptoms of gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr. 2007;45(5):530-7.



reflux)

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The costs of functional gastrointestinal disorders and related signs and symptoms in infants: a systematic

literature review and cost calculation for England

Journal: BMJ Open

Manuscript ID bmjopen-2016-015594.R2


Date Submitted by the Author: 20-Oct-2017

Complete List of Authors: Mahon, James; York Health Economics Consortium Lifschitz, Carlos; Hospital Italiano de Buenos Aires, Departamento de Pediatria

Ludwig, Thomas; Nutricia Research Thapar, Nikhil; Great Ormond Street Hospital For Children NHS Trust Glanville, Julie; University of York, York Health Economics Consortium Miqdady, Mohamad; Ped. GI, Hepatology & Nutrition Division Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates, Pediatrics Saps, Miguel; Nationwide Children’s Hospital, Columbus, Ohio, USA Seng Hock , Quak ; National University of Singapore, Singapore Lenoir-Wijnkoop, Irene; University of Utrecht, Utrecht, The Netherlands Edwards, Mary; University of York, York Health Economics Consortium Wood, Hannah; York Health Economics Consortium SZAJEWSKA, Hania; The Medical University of Warsaw, Dept of Paediatrics

<b>Primary Subject


Secondary Subject Heading: Gastroenterology and hepatology, Health economics, Paediatrics, Public health



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1

The costs of functional gastrointestinal disorders and

related signs and symptoms in infants: a systematic

literature review and cost calculation for England















Word count: 3,603

Tables: 3

Online supplement: 1

Corresponding author: Carlos Lifschitz, M.D.

Hospital Italiano de Buenos Aires

Buenos Aires, Argentina

[email protected]

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ABSTRACT



Study design: To estimate the cost of illness (COI) of infant FGIDs a two stage

process was applied: a systematic literature review, and a COI calculation. As no

pertinent papers were found in the systematic literature review, a “de novo” analysis

was performed. For the latter, the potential costs for the third party payer (the

National Health Service (NHS) in England) and for parents/carers for the treatment of

FGIDs in infants were calculated, by using publicly available data. In constructing the

calculation, estimates and assumptions (where necessary) were chosen to provide a

lower bound (minimum) of the potential overall cost. In doing so, the interpretation of

the calculation is that the true COI can be no lower than that estimated.

Results: Our calculation estimated that the total costs of treating FGIDs in infants in




counter remedies.








implementation.

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Strengths

• The costs calculation is focused on more recent studies and data to ensure

currency and most recent practice are reflected in terms of care of FGIDs and

related signs and symptoms.

• Where necessary, estimates and assumptions were always chosen to provide

consistently a lower bound of the potential cost.

Limitations




calculation.

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review. HW, JMG and TL designed the search strategy. CL, HS, IL-W, MM, MS, and

SHQ gave input to the search strategy and the inclusion and exclusion criteria. JMG

and JM defined the data extraction elements. JM, JMG, ME, and TL wrote the

protocol, CL, JM, JMG, ME, and TL wrote this manuscript. CL, HS, IL-W, MM, MS,





James Mahon.








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5

ABBREVIATIONS


COI Cost of illness


GI Gastrointestinal









UK United Kingdom



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INTRODUCTION



and symptoms without obvious structural or biochemical alterations.[1] Within the first

year after birth, such symptoms can be observed in up to 50% of infants.[2, 3]



approximately 30%, 20%, and 15%, respectively.[4] In addition, many children may

present with a combination of FGIDs and related signs and symptoms.[3, 4] Although



professionals (HCPs).[3, 4]


and algorithms have been developed for their practical management by HCPs.[1, 4-

6] These algorithms build on parental support, reassurance, and nutritional advice as






other treatments that are either contraindicated or not substantiated scientifically.[7]



parents.

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METHODS

The study employed a two stage methodology to estimate the cost of illness (COI) of

infant FGIDs, a systematic literature review, and a COI calculation. Here, we report

in detail on the latter.

Stage One

A systematic literature review was undertaken to identify any studies published in or

after 2005 that provided information on a) the frequency and volume of reported

treatments of FGIDs and related signs and symptoms (regardless of their

effectiveness; b) costs to third party payers and/or parents of infants with FGIDs and

related signs and symptoms of prescribed treatments, over the counter (OTC) or

home remedies, visits to health care professionals and other providers of

complementary and other forms of care, and changes in infant formula; c) loss of

income for parents/carers of infants with FGIDs and related signs and symptoms, or

the specific symptom combinations described above, through inability to return to

work, time taken off work, and out of pocket costs.




details of the review methods and protocol have been published in detail.[8] Studies



Stage Two –COI calculation for one country

Since the systematic review identified no research on COI for any country, we

performed a calculation for one country using evidence from stage one (the literature

review) where appropriate, and from readily available data sources. England was

chosen as an exemplar country due to the availability and quality of data on

healthcare resource use, both publicly and privately, and the availability of these data

in the English language.






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Prescription data























months.





been proven to be ineffective [9] and have frequent side effects.[10-12]








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between 10% and 40%.[13] A National Institute of Health Research funded ongoing

trial of supporting parents of infants with colic indicates an incidence of 1 in 5

infants.[14] Applying the 1 in 5 figure to the 697,852 infants born live in England and

Wales in 2015 means that approximately 140,000 infants in England experienced

colic in that year.











Hospital care













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for FGIDs.















the period 2014/15.

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RESULTS


The full review results are presented in the in a supplement to this manuscript

(Supplementary File). In total, 12364 records were identified from database

searching and 78 from additional resources. After the steps of duplicate removal,

title, abstract, and full text screen, 31 studies were identified that provided data about

treatments, signs and symptoms of FGID in infants. 3 further studies provided

additional data on young children in the USA.[15-17] 26 of the 31 eligible studies

were randomized controlled trials and five were case series.[8] Almost half (15) of

these studies were undertaken in Europe [18-32] (including three in the UK).[30-32]

Four studies were conducted in the USA [33-36], three in Australia [37-39], three in

Turkey [40-42], and one each in Brazil [43], Canada [44], China [45], Iran [46], Israel

[12] and Nigeria [47]. Twenty nine studies included infants with infantile colic and two

studies included infants with constipation. Several different interventions were

addressed in the eligible studies. We could not identify any study that addressed the

whole spectrum of costs of treating FGID in infants.

Stage Two –COI calculation for England

Prescription data







of £0.9 million.



Cost £ (millions)

Medicinal 521.2 5.8

Colic 115.1 1.1

Colief_Infant Dps 64.7 0.9

Dentinox_Infant Colic Dps 3.1 <0.1

Infacol_Susp 40mg/ml S/F 47.1 0.2

Nurse Harveys_Gripe Mix <0.1 <0.1

Woodward's_Gripe Water 0.2 <0.1

Constipation 24.8 <0.1

Glycerol Suppository Infants (1g) 23.9 <0.1

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Cost £ (millions)


0.9 <0.1


Gaviscon Infant_Sach 2g (Dual Pack) S/F (9/10 of total prescriptions)

381.4 4.7

Colic and regurgitation formulas 58.8 0.9


Colic 3.0 0.1 Grand Total 580.0 6.7



minutes, with a unit cost per half hour of £25[48] giving a cost of £3.5 million.



equate to a cost to the NHS of £26.0 million.[48] For the allergy and other special

infant formulas the cost of GP time would be £30.9 million.






2014/15 was £359.13.[49] The total cost of the admitted patient care was therefore

£9.3 million. This cost is only for bed days and does not include the cost of any

diagnostic procedures.




conditions was 5.7%.[50] We estimated the number of attendances due to GI

conditions in infants aged under one year by assuming that the proportion of

attendances due to GI conditions is the same across age groups. Evidence from the

USA identified in the literature review suggested that 9.4% of all Emergency

Department visits in the USA due to constipation were in those aged under 12

months. [16] If a similar pattern is seen in England, and for all FGIDs, then this

means that the estimated attendances we have calculated are likely to be a

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significant underestimate.



ICD10

code


admissions

Mean length of

stay

k21.9 Reflux 6717 1


newborn

136 1


childhood

4 11


r10.4 Colic 885 1





The reference cost of a NHS A&E visit in 2014/15 was £132.[49] So the total cost of

all visits for infants in 2014/15 was £63.7 million. If all these visits by infants were due

to FGIDs then this is the upper bound of what the cost of A&E services due to FGIDs



than £3.6 million.












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chiropractic services, physiotherapy, homeopathy, osteopathy, and acupuncture.[24,

27, 28, 30, 31] No data were identified in the literature on the scale of use of these

therapies. We contacted professional associations and regulatory bodies associated

with each therapy to request any data they might hold on this issue. However, none

were able to provide information for the analysis. The costs of these approaches are

therefore not stated, which constitutes an underestimate of the real costs.















formula)

£26.0


A&E visits £3.6



Total costs £72.3

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DISCUSSION



may do. Our systematic literature review reports a multitude of different treatments


reported interventions may still represent only a fraction of the remedies that are

being used on a daily basis. It is outside the scope of this review to evaluate the

efficacy of any intervention mentioned here, although for some OTC remedies it

appears that tolerance and safety data from clinical studies are lacking.



systematic literature review, we chose England as the focus of a COI calculation


resource use.












our estimates.


developed countries.[51] If this is the case for all age groups, then it would suggest

that the estimate for England is at the lower end compared to expenditure in other









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indicate areas where further research is required. The total cost presented here is

likely to be a significant underestimate of the true cost as lower bound estimates

were used where applicable, and several costs could not be adequately estimated

and were omitted from the calculation. Where necessary, estimates and assumptions

were chosen to provide consistently a lower bound of the potential cost.















preparations.[52]




The number and type of products sold to treat FGIDs suggested that some

physicians do not follow treatment guidelines. Some infants are being medicated

unnecessarily, which is potentially detrimental to patient health outcomes and

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definitely a wasted cost, either to the taxpayer or to parents. This may be the

consequence of parental demands, but may also be a gap on the provision of

parental reassurance. These findings support the impression of those co-authors

who are paediatric gastroenterologists practicing in different parts of the world (CL,

NT, MM, MS, SHQ, HS) who see in consultation infants with FGIDs who frequently

have been treated not in accordance to guidelines.







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ACKNOWLEDGEMENTS





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14. De Montfort University. Development and preliminary evaluation of an intervention package to support parents of excessively crying infants. Identifier: ISRCTN84975637. In: ISRCTN Registry [internet]. London:

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15. Sethi S, Mikami S, Leclair J, et al. Inpatient burden of constipation in the United States: an analysis of national trends in the United States from 1997 to 2010. Am J Gastroenterol 2014;109:250-6.

16. Sommers T, Corban C, Sengupta N, et al. Emergency department burden of constipation in the United States from 2006 to 2011. Am J Gastroenterol 2015;110:572-9.

17. Park R, Mikami S, LeClair J, et al. Inpatient burden of childhood functional GI disorders in the USA: an analysis of national trends in the USA from 1997 to 2009. Neurogastroenterol Motil 2015;27:684-92.

18. Dupont C, Rivero M, Grillon C, et al. Alpha-lactalbumin-enriched and probiotic-supplemented infant formula in infants with colic: growth and gastrointestinal tolerance. Eur J Clin Nutr 2010;64:765-7.

19. Coccorullo P, Strisciuglio C, Martinelli M, et al. Lactobacillus reuteri (DSM 17938) in infants with functional chronic constipation: a double-blind, randomized, placebo-controlled study. J Pediatr 2010;157:598-602.

20. Savino F, Ceratto S, Poggi E, et al. Preventive effects of oral probiotic on infantile colic: a prospective, randomised, blinded, controlled trial using Lactobacillus reuteri DSM 17938. Benef Microbes 2015;6:245-51.

21. Savino F, Cordisco L, Tarasco V, et al. Lactobacillus reuteri DSM 17938 in infantile colic: a randomized, double-blind, placebo-controlled trial. Pediatr 2010;126:e526-33.

22. Savino F, Palumeri E, Castagno E, et al. Reduction of crying episodes owing to infantile colic: A randomized controlled study on the efficacy of a new infant formula. Eur J Clin Nutr 2006;60:1304-10.

23. Savino F, Pelle E, Palumeri E, et al. Lactobacillus reuteri (American Type Culture Collection Strain 55730) versus simethicone in the treatment of infantile colic: a prospective randomized study. Pediatr 2007;119:e124-30.

24. Skjeie H, Skonnord T, Fetveit A, et al. Acupuncture for infantile colic: a blinding-validated, randomized controlled multicentre trial in general practice. Scand J Prim Health Care 2013;31:190-6.

25. Szajewska H, Gyrczuk E, Horvath A. Lactobacillus reuteri DSM 17938 for the management of infantile colic in breastfed infants: a randomized, double-blind, placebo-controlled trial. J Pediatr 2013;162:257-62.

26. Infante Pina D, Badia Llach X, Arino-Armengol B, et al. Prevalence and dietetic management of mild gastrointestinal disorders in milk-fed infants. World J Gastroenterol 2008;14:248-54.

27. Landgren K, Kvorning N, Hallstrom I. Acupuncture reduces crying in infants with infantile colic: a randomised, controlled, blind clinical study. Acupunct Med 2010;28:174-9.

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28. Reinthal M, Andersson S, Gustafsson M, et al. Effects of minimal acupuncture in children with infantile colic - A prospective, quasi-randomised single blind controlled trial. Acupunct Med 2008;26:171-82.

29. Bongers MEJ, de Lorijn F, Reitsma JB, et al. The clinical effect of a new infant formula in term infants with constipation: a double-blind, randomized cross-over trial. Nutr J 2007;6:8.

30. Browning M, Miller J. Comparison of the short-term effects of chiropractic spinal manipulation and occipito-sacral decompression in the treatment of infant colic: A single-blinded, randomised, comparison trial. Clin Chiropr 2008;11:122-29.

31. Hayden C, Mullinger B. A preliminary assessment of the impact of cranial osteopathy for the relief of infantile colic. Complement Ther Clin Pract 2006;12:83-90.

32. Miller J, Newell D. Prognostic significance of subgroup classification for infant patients with crying disorders: A prospective cohort study. J Can Chiropr Assoc 2012;56:40-8.

33. Salisbury AL, High P, Twomey JE, et al. A randomized control trial of integrated care for families managing infant colic. Infant Ment Health J 2012;33:110-22.

34. Keefe MR, Lobo ML, Froese-Fretz A, et al. Effectiveness of an intervention for colic. Clin Pediatr 2006;45:123-33.

35. Cirgin Ellett ML, Perkins SM. Examination of the effect of Dr. Brown's Natural Flow Baby Bottles on infant colic. Gastroenterol Nurs 2006;29:226-31.

36. Berseth CL, Johnston WH, Stolz SI, et al. Clinical response to 2 commonly used switch formulas occurs within 1 day. Clin Pediatr (Phila) 2009;48:58-65.

37. Hill DJ, Roy N, Heine RG, et al. Effect of a low-allergen maternal diet on colic among breastfed infants: a randomized, controlled trial. Pediatr 2005;116:e709-15.

38. Kianifar H, Ahanchian H, Grover Z, et al. Synbiotic in the management of infantile colic: a randomised controlled trial. J Paediatr Child Health 2014;50:801-5.

39. Sung V, Hiscock H, Tang MLK, et al. Treating infant colic with the probiotic Lactobacillus reuteri: double blind, placebo controlled randomised trial. BMJ 2014;348:g2107.

40. Ciftci EK, Arikan D. Methods used to eliminate colic in infants in the eastern parts of Turkey. Public Health Nurs 2007;24:503-10.

41. Arikan D, Alp H, Gozum S, et al. Effectiveness of massage, sucrose solution, herbal tea or hydrolysed formula in the treatment of infantile colic. J Clin Nurs 2008;17:1754-61.

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44. Chau K, Lau E, Greenberg S, et al. Probiotics for infantile colic: a randomized, double-blind, placebo-controlled trial investigating Lactobacillus reuteri DSM 17938. J Pediatr 2015;166:74-8.

45. Mi G-L, Zhao L, Qiao D-D, et al. Effectiveness of Lactobacillus reuteri in infantile colic and colicky induced maternal depression: a prospective single blind randomized trial. Antonie van Leeuwenhoek 2015;107:1547-53.

46. Moravej H, Imanieh MH, Kashef S, et al. Predictive value of the cow's milk skin prick test in infantile colic. Ann Saudi Med 2010;30:468-70.

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1

SUPPLEMENTAL MATERIAL TO

Functional gastrointestinal disorders and related signs and

symptoms in infants: discrepancies between actual and estimated

costs of recommended treatments in England

Authors: James MAHON1*

, Carlos LIFSCHITZ2*

, Thomas LUDWIG3, Nikhil THAPAR

4, Julie GLANVILLE

1,

Mohamad MIQDADY5, Miguel SAPS

6, Seng Hock QUAK

7, Irene LENOIR-WIJNKOOP

8, Mary EDWARDS

1,

Hannah WOOD1, Hania SZAJEWSKA

9


1 York Health Economics Consortium, University of York, York, UK 2 Hospital Italiano, Buenos Aires, Argentina 3 Nutricia Research, Singapore 4 Great Ormond Street Hospital, London, United Kingdom 5 Pediatric Gastroentrology, Hepatology & Nutrition Division Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates 6 Nationwide Children’s Hospital, Columbus, Ohio, USA 7 National University of Singapore, Singapore 8 University of Utrecht, Utrecht, The Netherlands 9 Medical University of Warsaw, Warsaw, Poland

The systematic review protocol is published in:

Glanville J, Ludwig T, Lifschitz C, Mahon J, Miqdady M, Saps M, Hock Quak S, Lenoir-

Wijnkoop I, Edwards M, Wood H, Szajewska H. Costs associated with functional

gastrointestinal disorders and related signs and symptoms in infants: a systematic review

protocol. BMJ Open. 2016 Aug 24;6(8):e011475. doi: 10.1136/bmjopen-2016-011475

This document presents the results of the systematic review.

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Abbreviations

AACP Acupuncture Association of Chartered Physiotherapists

ALSPAC Avon Longitudinal Study of Parents and Children

AWMA Academy of Western Medical Acupuncture

BMAS British Medical Acupuncture Society

BMJ British Medical Journal

CAM Complementary and Alternative Medicine

CEA Cost Effectiveness Analysis

CMP Cows' Milk Protein

COI Cost of Illness

COL Cost of living

CRD Centre for Reviews and Dissemination

DARE Database of Abstracts of Reviews of Effects

EED Economic Evaluation Database

ESPGHAN European Society for Pediatric Gastroenterology, Hepatology, and Nutrition


GER Gastro-esophageal Reflux

GERD Gastro-esophageal Reflux Disease

GOR Gastroesophageal Reflux

GORD Gastroesophageal Reflux Disease

GSRS Gastrointestinal Rating Scale


HTA Health Technology Assessment

IBS Irritable Bowel Syndrome

ISPOR International Society for Pharmacoeconomics and Outcomes Research

JAMA Journal of the American Medical Association

NASPGHAN North American Society for Pediatric Gastroenterology, Hepatology, and

Nutrition

NHS National Health Service

NICE National Institute for Health and Care Excellence

OTC Over the Counter

PLOS Public Library of Science

PPI Proton Pump Inhibitor

PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses

RCT Randomised Controlled Trial

REPEC Research Papers in Economics

REST Reassurance, Empathy, Support, Time out



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Section 1: Results of the Systematic Review

1.1 LITERATURE SEARCH RESULTS

The searches identified 12,442 records (Table 1.1). Following deduplication 9,479 records

were assessed for relevance.

Table 1.1: Literature search results by resource

Resource or study identification method Number of records identified

MEDLINE and MEDLINE In-Process 2793

PubMed (for non-MEDLINE records only) 1395

Embase 6500

PsycINFO 746

NEXIS 528

Database of Abstracts of Reviews of Effects (DARE) 109

Health Technology Assessment Database (HTA Database) 11

NHS Economic Evaluations Database (NHS EED) 25

CEA Registry 0

NHS Evidence Search 16

OAISTER 240

RePEc 1

Conference hand-searches 24

Contacting conference abstract authors 8

Checking reference lists 45

Other 1

Total number of records 12,442

Total number of records following deduplication 9,479

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Figure 1.1: Record selection process (PRISMA)

SC

RE

EN

ING

IN

CL

UD

ED

E

LIG

IBIL

ITY

D

EN

TIF

ICA

TIO

N

Records identified through database

searching

(n = 12364)

Additional records identified through

other sources

(n = 78)


(n = 9479)

Records screened based

on title and abstract

(n = 9479)

Records excluded after title

and abstract assessment

(n = 9318)

Full-text documents

assessed for eligibility

(n = 161)

Full-text documents

excluded

(n = 125)

Studies included in the

review

(n = 34)


Unavailable potentially

relevant studies not included

in the review

(n = 1)

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1.2 STUDY CHARACTERISTICS

34 studies (reported in 35 documents) were identified reporting treatments for FGIDs and as

well as related signs and symptoms, in infants younger than one year of age. One study

was reported in two documents [1, 2]. Full details of the study characteristics of the included

studies are reported in Table 1.2.

1.2.1 Study design

26 of the 34 studies (77%) were RCTs [2-27], including two crossover trials [4, 7] and a

quasi-randomised trial [19]. Three of the studies [28-30] were cost of illness studies,

although only of specific aspects of interventions for infant FGID. The remaining five studies

were cohort, case series and cross sectional studies [31-35].

1.2.2 Study location

Almost half (15/34) [2, 7, 8, 11-13, 19, 21-25, 27, 33, 34] of the included studies were

conducted in Europe, including three in the UK [8, 13, 34]. Seven studies were conducted in

the USA [6, 10, 15, 20, 28-30] ; three in Australia [14, 16, 26]; three in Turkey [3, 5, 32]; and

one each in China [17], Brazil [4] , Israel [31], Canada [9], Iran [18] and Nigeria [35].

1.2.3 Perspective

Of the 34 included studies, the majority assessed data from a patient/parent and healthcare

perspective (32/34, 94%). Two studies assessed data from only the patient/parent

perspective [19, 32].

1.2.4 Study objectives

Study objectives varied across the 34 included studies, but the majority sought to evaluate

an intervention in infants with colic or functional constipation.

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Table 1.2: Systematic review: Study characteristics

Study reference




Akcam 2006 [3]


To study efficacy of 30% glucose solution in the treatment of infant colic

Mar – Dec 2003

“Typical infant colic” – minimum of 3h crying per day, 3 days per week for the last 3 weeks

Alves 2012 [4]

Brazil RCT Patient and healthcare provider

To compare the efficacy of Mentha piperita with

simethicone in the treatment of infant colic

Mar – Dec 2011

Infants aged 15 to 60 days, exclusively breastfeeding. IC was characterised as

paroxysmal attacks or irritability, restlessness, or crying for at least 3 hours a day, and

occurring more than 3 days a week for a period of 3 weeks

Arikan 2008 [5]


To evaluate the effectiveness of massage, sucrose solution,

herbal tea or hydrolysed formula, each used individually

in the treatment of infantile colic

Jan – Jun 2005

Infant between 4–12 weeks of age with typical infantile colic as defined by Wessel et al.; born

at term or preterm (gestational age 37–42 weeks) with a birth weight between 2.5 and 4

kg; appropriate gain in weight, length and head circumference and normal psychomotor

development on paediatric physical examination

Aviner 2010 [31]

Israel Case series Patient and healthcare provider

To report on 11 infants who presented with an apparent life-

threatening event after ingestion of Gali-col Baby, a homeopathic agent indicated

for “infantile colic”

Jan 2005 – Aug 2008

A computerised search was conducted for admissions with 1 of the following diagnoses:

apparent life-threatening event, apnea, choking, cyanotic spell or episode, and sudden infant death syndrome (of these 11 patients were

found to have taken Gali-col)

Berseth 2009 [6]


To examine the effects of a partially hydrolysed cow’s milk protein, low lactose formula or

a soy-based lactose-free formula on infant fussiness

(defined as general irritability, discontentment, or discomfort that is difficult to soothe) and other symptoms of formula

intolerance (crying, gas, occurrences of spit-up,

diarrhoea, constipation, and

NR

Singleton births, 7-63 days of age, with a minimum birth weight of 2500 g, solely received a full-lactose, intact cow’s milk protein formula

for 7 days before randomisation, and were parent-identified as very fussy or extremely fussy in the baseline tolerance evaluation

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Study reference




stool patterns) in term infants parent identified as very or

extremely fussy

Bongers 2007 [7]

The Netherlands

RCT Patient and healthcare provider

To examine the effects of a new infant formula in constipated infants

Apr 2002 – Jan 2004

Otherwise healthy, term infants with constipation, between 3 – 20 weeks of age, who received at least 2 bottles of milk-based formula

per day

Browning 2008 [8]


To compare the short-term effects of chiropractic spinal manipulation and occipito-

sacral decompression in the treatment of infant colic

NR

Less than 8 weeks of age, born with birth weight equal to or more than 2500 g, born at or after 38 weeks gestation, cry for 3 h or more per

day with one or more inconsolable crying episodes for at least four of the previous 7 days and show typical restless behaviour (i.e. motor

unrest, flexing knees against abdomen, extending the trunk, neck, and extremities). The parent/guardian had to be fluent and

literate in the English language.

Chau 2015 [9]

Canada RCT Patient and healthcare provider

To investigate the effectiveness of Lactobacillus reuteri DSM 17938 for the treatment of infantile colic in breastfed

infants, compared with placebo

Feb 2012 – Apr 2014

Diagnosis of infantile colic (i.e, crying or fussy/gassy episodes ≥3 hours/day for ≥3

days/7 days, as defined by a modified definition of Wessel criteria); age 3 weeks to 6 months;

exclusively breastfed; term delivery (≥37 weeks gestation at birth); 5-minute Apgar score ≥7;

and birth weight ≥2500 g

Ciftci 2007 [32]

Turkey Cross

sectional Parents

To assess the methods used by mothers to eliminate colic in their infants and to determine

the efficacy of the various methods

Jan –Feb 2005

Infants aged 1–3 months registered at a primary health centre

Cirgin 2006 [10]


To examine the effect of using Dr. Brown’s Natural Flow baby bottles to feed the colicky infant on the mean time per day the infant spent crying, fussing,

and sleeping

NR 7 months old or less and receiving the majority

of their feedings by bottle

Coccorullo Italy RCT Patient and To evaluate the beneficial Jan – Dec Formula-fed infants >6 months of age referred

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Study reference





effects of Lactobacillus reuteri (DSM 17938) in infants with

functional chronic constipation

2008 for functional chronic constipation to the Gastrointestinal Endoscopy and Motility Unit of

the Department of Pediatrics, University ‘‘Federico II’’ of Naples

Dupont 2010 [12]

France RCT Patient and healthcare provider

To evaluate the nutritional adequacy, the gastrointestinal

tolerance and the effect on colic of an α-lactalbumin-enriched and probiotic-

supplemented infant formulae, in infants with colic

NR

Infants had to be born at term, aged 3 weeks to 3 months, weaned, with normal growth and with more than 3 weeks of crying periods, at least 3 h per day, 3 days per week (Wessel et al., 1954 [36]), with or without abdominal distension, gas

and regurgitation

Hayden 2006 [13]


To investigate the effect of cranial osteopathic

manipulative treatment on the pattern of increased crying,

irritability and disturbed sleep associated with infantile colic

NR

Infants between 1 and 12 weeks of age, not been previously treated osteopathically,

exhibited signs of infantile colic and no signs or symptoms indicative of other disease

Hill 2005 [14]


To evaluate the effect of a hypoallergenic maternal

elimination diet on persistent crying among breastfed infants

presenting with colic

2000 – 2002

Exclusively breastfed infants <6 weeks of age with colic; well, term infants (gestational age of

37 weeks) who were the result of a normal singleton pregnancy

Infante Pina 2008

[33] Spain

Cross sectional


To assess the effectiveness of dietetic treatment with the Novalac range of formulas

specifically developed for mild gastrointestinal disorders.

NR

Infants up to four months of age fed with artificial milk formulas; the presence of mild gastrointestinal disorders; the possibility of

feeding the infants with some product of the Novalac line of formulas; continuation of these formulas on an exclusive basis for at least 30

days.

Keefe 2006 [15]


To evaluate an individualized intervention program for infant

irritability or colic NR

Full term, healthy low-risk infants between the ages of 2 and 6 weeks, and living within a 2-

hour radius of the metropolitan area.

Kianifar 2014 [16]


To determine efficacy of synbiotic in reducing average infant crying time at day 7 and

day 30 after starting

NR

Healthy breastfed infants aged 2 weeks to 4 months with infant colic defined as per Wessel’s criteria based on care giver’s symptom records

diary.

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Study reference




intervention

Landgren 2010 [2]

Sweden RCT Patient and healthcare provider

To investigate whether acupuncture reduces the

duration of crying in infants with colic

Nov 2005 – Feb 2007

Healthy infants, born after gestational week 36, not treated with dicyclomine and fulfilling the

modified Wessel criteria for colic: ‘crying/fussing for at least 3 hrs a day, occurring 3 days or

more in the same week’

Mi 2015 [17]

China RCT Patient and healthcare provider

To explore the role which L. reuteri could play in the

management of infant colic

Feb 2013 – Apr 2014

Infants less than 4 months of age weighing between 2.5 and 4kg and exclusively or

predominantly breastfed

Miller 2012 [34]

UK Cohort Patient and healthcare provider

To determine any possible justification of the use of three

priori clinically determined categories of excessively crying infants, based on

differences in parent reported outcomes after a course of

chiropractic treatment

Jul 2007 – Mar 2008

All babies between the ages of one day and 18 weeks who presented with excessive crying to a

UK chiropractic teaching clinic between July 2007 and March 2008

Infants included if they could be categorised

using clinical signs and symptoms into one of the three classification groups; infant colic, irritable Infant syndrome of musculoskeletal origin or inefficient feeding crying infant with

disordered sleep.

Moravej 2010 [18]

Iran RCT Patient and healthcare provider

To investigate the value of skin prick testing (SPT) in the

diagnosis of cow’s milk allergy in patients with infantile colic

NR Breast-fed infants with history of infantile colic

(diagnosed based on the Wessel criteria) between the ages of 3 weeks and 3 months

Oshikoya 2009 [35]

Nigeria Cross

sectional


To determine the knowledge of Nigerian mothers about colic,

their home-based management, extent of self-

medication for the infants with colic and the types of medicines involved

Apr – Sep 2006

Mothers who brought their infants for vaccination to a primary health care centre

Park (2015)

USA

COI (retrospective

database analysis)

Healthcare provider

To analyze the inpatient burden of common childhood FGIDs

including constipation, abdominal pain, IBS, dyspepsia, abdominal

1997-2009

All infants in whom constipation, abdominal pain, dyspepsia, IBS, abdominal migraine, fecal

incontinence was the primary discharge diagnosis from 1997, 2000, 2003, 2006 and

2009

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Study reference




migraine, and fecal incontinence

Reinthal 2008 [19]

Sweden RCT Patient

To evaluated the effects of light needling on crying and the pain

related behaviour in children with infantile colic

NR

New born, breastfed children with infantile colic (as described by Wessel et all, 1954 [36])

diagnosed by doctors and registered at one of 21 Child Welfare Clinics within an area of

western Sweden.

Salisbury 2012 [20]


To examine the effectiveness of a unique model of integrated care for the treatment of infant

colic.

NR

Participants were largely self-referred after seeing brochures in the office of their

healthcare provider or were referred from a Specialty Clinic. Infants were required to be:

singleton, born at or after 37 weeks gestational age, aged 4 to 8 weeks of age at the time of

enrolment, had no more than 4 days of special nursery care after birth, no congenital

anomalies, no exposure to illegal drugs in utero, and no suspicion of foetal alcohol syndRome. The family needed to be English-speaking and

have a working telephone in the home. Mothers were over 17 years old and had no

history of psychiatric hospitalization or involvement with Child Protective Services.

The infant needed to be otherwise healthy, and meet the “Wessel Rule of 3s” criteria by parent report at the time of the call: crying for at least 3 hr a day for at least 3 days a week for at least 3

weeks.

Savino 2015 [21]


To evaluate the efficacy of orally administered L. reuteri DSM 17938 with vitamin D3 from the age of ten days in

reducing parental discomfort due to infantile colic in a

population of otherwise healthy infants.

2012 - 2013

New borns aged less than 10 days of life, with gestational age between 37 and 42 weeks, birth

weight from 2,500 to 4,300 g, and normal physical examination

Savino Italy RCT Patient and To test the efficacy of 2008 - 2009 Breast fed infants diagnosed with infantile colic

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Lactobacillus reuteri on infantile colic and to evaluate its relationship to the gut

microbiota

according to the following modified Wessel’s criteria: episodes of fussy crying that lasted 3

hours a day and episodes that lasted for 3 days in the 1 week before enrolment. All were born

at term, adequate for gestational age (birth weight: 2500 – 4000 g), and aged 2 to 16 weeks at recruitment. Only exclusively

breastfed infants were enrolled to prevent variability in the intestinal microbiota caused by

diet.

Savino 2006 [23]


To confirm the role of new formula in colicky infants with a

randomized prospective controlled trial.

2002 - 2003

Gestational age between 37 and 42 weeks, normal birth weight (>2500 g), regular weight

gain (>=150 g/week) and normal physical examination

Savino 2007 [24]


To test the hypothesis that oral administration of Lactobacillus

reuteri in a prospective randomized study would

improve symptoms of infantile colic.

2004 - 2005

Breastfed infants with a diagnosis of infantile colic Patients 21 to 90 days of age, appropriate for gestational age with birth weights between

2500 and 4000 g, with colic symptoms ( 3 hours of crying on 3 days in the week) with debut 6

+/-1 days before enrolment

Sethi (2014)

USA

COI (retrospective

database analysis)

Heatlhcare provider

To evaluate patient admission rates, length of stay and costs

for constipation in the USA 1997-2010

Any admission with ICD-9-CM primary diagnostic codes 564.0-564.9

Skjeie 2013 [25]

Norway RCT Patient and healthcare provider

To test the hypothesis that acupuncture treatment has a clinically relevant effect for

infant colic

2009 - 2012 Fulfilled Wessel’s criteria [36] and were born at

full term.

Sommers (2015)

USA

COI (retrospective

database analysis)

Heatlhcare provider

To evaluate ED visits and costs for constipation in the USA

2006-2011 Any admission with ICD-9-CM primary

diagnostic codes 564.0-564.9

Sung 2014 [26]


To determine whether the probiotic Lactobacillus reuteri DSM 17938 reduces crying or fussing in a broad community

2011 - 2012

Healthy term infants less than 13 weeks of age with infant colic, defined by modified Wessel’s criteria of crying or fussing for three hours or

more a day for three days or more over seven

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Study reference




based sample of breastfed infants and formula fed infants

with colic aged less than 3 months

days. Fussing was defined as “behaviour that is not quite crying but not awake and content

either.”

Szajewska 2013 [27]

Poland RCT Patient and healthcare provider

To determine whether administration of Lactobacillus

reuteri (L reuteri) DSM 17938 is beneficial in breastfed infants

with infantile colic

2010 - 2011

Full term infants aged <5 months with infantile colic (defined as crying episodes lasting 3 or more hours per day and occurring at least 3

days per week within 7 days prior to enrolment), who were exclusively or predominantly (>50%)

breastfed.

Key: ED – Emergency department; RCT: Randomised controlled trial; USA: United States of America; CMP: Cows’ Milk Protein; COI: Cost of illness

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1.3 PARTICIPANTS’ CHARACTERISTICS

1.3.1 Number of trial participants

Of the 26 RCTs [2-27], nine [3, 4, 7, 8, 10, 11, 13, 17, 19] included fewer than 50

participants; ten trials [2, 9, 12, 16, 18, 20, 22, 24, 25, 27] included between 50 and 100

participants and seven trials [5, 6, 14, 15, 26, 32, 34] included between 101 and 200

participants.

Of the five case series studies, study numbers ranged from 11 [31] to 1441 [33]. Two case

series studies included between 150 and 190 patients [32, 34] and another included 800

patients [35].

1.3.2 Age

All included studies were required to investigate treatments, signs and symptoms in infants

less than 12 months old. The youngest participant was one day old, and the eldest was 12

months old. One COI study included patients aged over 12 months but data for patients

under 12 months of age could be isolated in the analysis [30].

1.3.3 Sex

Among the studies that reported the number of males overall, the percentage of males

ranged from 36% [31] to 79% [13] with an average percentage of males of 53%.

Among the studies that reported the number of males for treatment and control groups

separately, treatment groups ranged from 44% [26] to 65% [19, 27] males, while control

groups had from 48% [20, 21, 23] to 59% [26] males.

Four studies did not report the number of males [4, 12, 16, 18].

1.3.4 FGID description

The majority of studies (27/34, 80%) included participants with infantile colic. Four studies

included participants with constipation [7, 11, 28, 29], one had participants with a range of

FGIDs including constipation and dyspepsia [30] and one trial described participants as

having mild gastrointestinal disorders including colic, regurgitation, diarrhoea and

constipation [33].

1.3.5 ROME criteria met

Seventeen of the 34 included studies met the ROME III criteria (17/34, 50%) [4, 7-9, 11, 12,

14, 20, 22-26, 28-30], seventeen studies did not explicitly meet the ROME III criteria.[2, 3, 5,

6, 10, 13, 15-18, 21, 31, 33-35].

Full details of the participants’ characteristics are reported in Table 2.3..

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Table 1.3: Systematic review: Participants’ characteristics

Study ID Number of participants Age Sex

FGID description ROME III criteria Min age Max age % = Male

Akcam 2006 [3]

25 Randomised 28

Analysed (16 Treatment, 12 Control)

NR NR Overall: 48% Infantile Colic No

Alves 2012 [4] 30 8 days 56 days NR Infantile Colic Yes

Arikan 2008 [5] 175

(35 x 4 treatment groups, 35 control)


Aviner 2010 [31] 11 Treatment,

11 matched controls 14 days 49 days Overall: 36% Infantile Colic No

Berseth 2009 [6] 159



Bongers 2007 [7] 38


0.7 months 5 months Overall: 50% Constipation Yes

Browning 2008 [8] 43


NR 8 weeks Overall: 63% Infantile Colic Yes

Chau 2015 [9] 52


31 days 51 days Overall: 48% Infantile Colic Yes

Ciftci 2007 [32] 186 1 month 3 months Overall: 52% Infantile Colic Unclear

Cirgin 2006 [10] 36 NR 7 months Overall: 48% Infantile Colic No


44 (22 Treatment,

22 Control) 6 months NR Overall: 55% Constipation Yes

Dupont 2010 [12]



3 weeks 3 months NR Infantile Colic Yes

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Hayden 2006 [13]




Hill 2005 [14]



2.9 weeks 8.6 weeks Overall: 60% Infantile Colic Yes


1441 1 week 4 months Overall: 52%

Mild-gastrointestinal disorders including colic, regurgitation, diarrhoea

and constipation

No

Keefe 2006 [15] 121 2.6 weeks 7.7 weeks Overall: 50% Infant irritability; Colic No

Kianifar 2014 [16] 50



Landgren 2010 [2]


44 Control)

81 Analysed (43 Treatment,

38 Control)


Mi 2015 [17]

42 Randomized (21 Treatment 21 Placebo);

39 Analysed

(20 Treatment, 19 Placebo)

Mean: 29.7 days 4 months Overall: 56% Infantile Colic No

Miller 2012 [34]

158 (Colic = 77;

Infant syndrome of musculoskeletal origin =

56; inefficient feeding crying


1 day 18 weeks Overall: 57%

Infant colic, irritable Infant syndrome of

musculoskeletal origin or inefficient feeding crying


No

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Study ID Number of participants Age Sex FGID description ROME III criteria = 25)

Moravej 2010 [18] 77

(35 Treatment, 42 controls)


Oshikoya 2009 [35]

800 Mothers: 15 years

old Infants: 1 day

Mothers: 40 years old

Infants: 12 months Overall: 52% Infantile Colic No

Park (2015) [30]

4,436,817 discharges in 1997;

4,600,709 discharges in 2009

0 to 12 months 51% (all ages)

Functional GI disorders: chronic constipation,

abdominal pain, irritable bowel syndrome,

dyspepsia, abdominal migraine, fecal incontinence

Yes

Reinthal 2008 [19]

40 (20 Treatment,

20 Control)

Treatment: 1 week Control: 3 weeks

Treatment: 11 weeks

Control: 25 weeks


Infantile Colic No

Salisbury 2012 [20]

62 (31 Treatment,

31 Control) 4.1 weeks 10.5 weeks


Infantile Colic Yes

Savino 2015 [21] 105


NR Overall: <10 days Treatment: 49%

Control: 48% Infantile Colic No

Savino 2010 [22] 50


NR: median treatment:

32.5 days (21) Control: 28.5 days

(21)

NR Treatment: 60%


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Savino 2006 [23]

267 Randomised, 199 Analysed (96 Treatment, 103 Control)

Treatment: mean 1.39 months (±0.84) Control: mean 1.29

months (±0.77)

NR Treatment: 52%


Savino 2007 [24]

90 Randomised 83 Analysed



Treatment: 80 days

Control 74 days


Infantile Colic Yes

Sethi 2014 [29] 20% of admitted population

in 12 months 0-12 months

38% 1997 39% 2010

Constipation (ICD-9-CM codes 564.0-564.9)

Yes

Skjeie 2013 [25] 84


Treatment: 3 weeks Control: 3 weeks

Treatment: 13 weeks

Control: 9 weeks


Infantile Colic Yes

Sommers 2015 [28]

20% of all ED visits in 12 months

0-12 months NR Constipation (ICD-9-CM

codes 564.0-564.9) Yes

Sung 2014 [26]


82 Control); 127 Analysed

Treatment: mean 7.5 weeks (±2.9)

Control: mean 6.9 weeks (±2.5)

NR Treatment: 44%


Szajewska 2013 [27]

80 (40 Treatment,

40 Control)


Treatment: 81 days

Control: 69 days


Infantile Colic Yes

Key: NR: Not reported

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1.4 INTERVENTIONS AND COMPARATORS

1.4.1 Intervention

Several different interventions were investigated across the 31 included studies that

considered interventions.

Ten studies investigated the impact of probiotic supplementation [9, 11, 12, 16, 17,

21, 22, 24, 26, 27];

Four studies used particular types of infant formula [6, 7, 23, 33];

Three studies used multiple types of interventions (alone or in combination) [5, 32,

35];

Three studies used acupuncture [2, 19, 25];

Three studies used chiropractic treatment [8, 13, 34];

Two studies changed the maternal diet [14, 18];

Two studies used natural remedies [4, 10];

One study used glucose [3];

Two studies used parental counselling [20];

One study used a homeopathic remedy [31].

1.4.2 Adverse events from an intervention

The majority of intervention studies reported that there were no side effects (15/31) from the

intervention under investigation, or did not report whether patients experienced any side

effects (12/31).

Four studies reported side effects associated with interventions. One study investigated

adverse events in infants receiving Gali-col Baby, a homeopathic remedy, and showed that 9

of the 11 participants had at least two adverse event symptoms [31].

Three studies investigating formulas reported side effects; in one study a soy based formula

was associated with adverse events in 50% of participants [6] while a second study

investigated a range of formulas belonging to the Novalac line (Anti-Colic, Anti-

Regurgitation, Anti-Diarrhoea, Anti-Constipation) and reported that 3.9% of infants suffered

an adverse event, most frequently affecting the digestive tract (1.4%), including diarrhoea

and constipation.[33] In a third study, a probiotic enriched formula reportedly caused

gastrointestinal side effects in 44% of infants and 15% experienced feeding-related side

effects.[12]

1.4.3 Comparator

Of the 26 RCTs with comparator groups, nine trials compared their interventions with

placebo [3, 9-11, 16, 17, 22, 25, 27]; eight compared interventions to standard care [2, 7, 12,

14, 15, 18-20]; seven compared their interventions to an alternative intervention [4, 6, 8, 21,

23, 24, 26] and two used no comparator intervention [5, 13].

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1.4.4 Adverse events from the comparator treatment

Three studies reported side effects associated with comparator treatments.[6, 12, 22] One

study investigated adverse events in 77 infants randomised to a comparator group who

received a partially hydrolysed cow’s milk protein, low lactose formula. 44 participants (58%)

had at least one adverse event [6].

A second study investigated adverse events in 24 infants randomised to a comparator group

who received a control formula (not enriched with probiotics as per the intervention) and

found that 67% of the comparator group experienced GI side effects including constipation,

vomiting, colitis, regurgitation and flatulence [12].

A third study investigated adverse events in 25 infants randomised to a placebo comparator

group. Compared to the one infant in the probiotic intervention group who developed rhinitis,

four infants in the placebo group experienced an adverse event including eczema, fever,

otalgy and gastroesophageal reflux [22].

1.4.5 Length of treatment

The length of treatment varied across the included studies, but overall ranged from one to

four weeks.

Full details of the interventions and comparators of the included studies are reported in

Table 1.4.

1.4.6 Cost of illness studies

Two of the cost of illness studies reported on hospital care for infants with functional

constipation [28, 29] in the United States based upon retrospective analysis of a database

covering 20% of all admissions and ED attendances. One study [28] reported 50,934 ED

attendances for infants with constipation at a cost of $2470 per attendance – although the

cost was based upon all attendances for adults and children. The second study [29] reported

499 hospital admissions for infants with constipation in 2010 at a cost of $17,518 per

admission but again this cost was for children and adults.

The third cost of illness study [30] also reported an analysis of a large databse of hospital

admissions, but for a range of FGIDs including constipation and abdominal pain. The rate of

discharge for infants aged under 12 months was 0.8 per 10,000 discharges for constipation,

1.0 per 10,000 discharges for abdominal pain and 0.1 per 10,000 discharges for dyspepsia.

Costs per discharge were provided but covered all patient under 18 years of age. Details of

the cost of illness studies are reported in Table 1.5.

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Table 1.4: Systematic review: details of interventions and comparators





Length of treatment

Akcam 2006 [3]

30% glucose solution 1ml drop – frequency

unclear None

Placebo - distilled water

1ml drop - unclear how

often None

NR - at least 8 days

Alves 2012 [4]

Mentha piperita 1 drop per kg body

weight daily None Simethicone

Liquid drops - 2.5 mg per kg body weight

daily

None

7 days for each

treatment with a

washout period of 3

days in between

Arikan 2008 [5]

1) massage, 2) sucrose solution, 3) herbal tea and

4) hydrolysed formula

1) Parents were advised to administer massage twice a day

for 25 minutes duration during

symptoms of colic, 2) 2 ml of 12%

solution twice a day at 5 pm and 8 pm,

3) fennel tea was administered at a

dose of 35 ml (maximum dose of

150 ml) three times a day,

4) hydrolysed formula (dose not reported)

NR Control (no intervention)

NA NR 1 week

Aviner 2010 [31]

Gali-col Baby (homeopathic remedy)

The manufacturer’s recommended dose is “up to 5 drops which might be repeated

once in 15 minutes or

All 11 patients had an ALTE. 9/11 (81.8%) infants who

received Gali-col

NA NA NA NA

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Length of treatment

according to the physician or pharmacist

instructions.” The amount of Gali-col Baby administered was recorded for 8

patients. For 3 patients, it was much

greater than the manufacturer’s

recommended dose, 4 other infants received the drug several times a day, and 1 patient

received a single recommended dose.

Baby showed at least 2

symptoms of an ALTE (this may be misleading because only

patients with an ALTE were

included in this study) Six

patients were hospitalised for 1 day, four were hospitalised for 2 days, and 1

was hospitalised for 3 day

Berseth 2009 [6]

Soy-based formula (Soy; Enfamil, ProSobee, LIPIL)

NA

41 (50% ) experienced at least 1 adverse

event

Partially hydrolysed cow's milk

protein, low-lactose formula

NA

44 (58%) experienced at least 1 adverse

event: (P = 0.34)

28 days

Bongers 2007 [7]

A new infant formula (NF; Nutrilon Omneo, Nutricia

Nederland BV, Zoetermeer, the Netherlands) which

contains modified vegetable oil with a high proportion

(41%) of palmitic acid at the sn-2 position, a mixture of prebiotic oligosaccharides, partially hydrolysed whey

protein and a reduced lactose content

NA No serious

adverse effects Standard formula

NA No serious

adverse effects

Two - 3 week treatment periods

Browning Spinal manipulative therapy Treatment was given None Occipito-sacral Treatment None 2 weeks

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Length of treatment

2008 [8] 2 -3 times per week, for 2 weeks, or less if

the symptoms resolved

decompression was given 2 - 3 times per week, for 2 weeks, or less if the symptoms resolved

Chau 2015 [9]

Probiotic L reuteri DSM 17938 (10

8 cfu)

5 drops orally, once daily

None

Placebo - the same excipient ingredients but without the live

bacteria

5 drops orally, once

daily None 21 days

Ciftci 2007 [32]

Treatments used by parents included: Taking the infant to a calm and dark room; holding the infant in their arms; rocking the infant;

positioning the infant; giving a massage to the infant;

warming the infant; having the infant listen to music;

giving the infant fennel tea; giving the infant anise;

giving the infant simethicone (metsil); taking the infant to

the hospital; giving the infant a sweet drink; giving the

infant lemon water; stimulating the rectum;

giving the infant olive oil; Using suppositories

NA NR NA NA NR NA

Cirgin 2006 [10]

Dr. Brown's Natural Flow baby bottle

NA NR Placebo baby

bottle NA NR 14 days


Probiotic L reuteri (DSM 17938) (10

8 cfu)

5 drops, once daily None Placebo Not explicitly

stated None 8 weeks

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Length of treatment

Dupont 2010 [12]

α-lactalbumin-enriched and probiotic-supplemented

infant formula (Lactobacillus rhamnosus, Bifidobacterium

infantis)

NA

44% experienced GI-

side effects; 15%

experienced feeding related

side effects (‘feeding-related’ GI side effects were: vomiting (one infant), colitis (one

infant)

Control formula (not enriched in α-lactalbumin, with a higher quantity of

proteins and lactose, and

neither probiotics nor

starch)

NA

67% experienced GI-side effects;

85% experienced feeding related

side effects ('feeding related’ GI side effects

were: constipation (five), vomiting (four), colitis

(one), regurgitations

(three) and flatulence (one

infant)

1 month

Hayden 2006 [13]

Cranial osteopathic manipulation

Once a week NR No treatment

Once a week (all infants

were brought to the

osteopathic clinic)

NR 4 weeks

Hill 2005 [14]

Low-allergen maternal elimination diet (mothers

excluded all foods containing dairy products, soy, wheat, eggs, peanuts,

tree nuts, and fish from their diet. Their diet included a

rice milk drink, meats, vegetables, fruits, and

cereals (corn and rice). A calcium supplement (1.2 g/day) was prescribed.

Mothers were supplied with a rice-based drink in powder form (500 mL/day), as well

NA NR

Control diet that included these foods (Mothers received 7 days of rations of a soy and cow’s milk powder

mixture to make 500 mL of a milk

drink per day (equivalent to 200 mL of soy

milk and 300 mL of cow’s milk). Mothers were

NA NR 1 week

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Length of treatment

as a daily supply of fresh rice bread)

asked to eat 1 serving of peanuts, 1 serving of

wheat, and 1 chocolate muesli

bar per day. Mothers were encouraged to maintain their usual intake of

vegetables, meats, rice, and other cereals)


A range of formulas belonging to the Novalac

line (Anti-Colic, Anti-Regurgitation, Anti-

Diarrhoea, Anti-Constipation)

NR

3.9% suffered an adverse event. Most

frequent affected the

digestive tract (1.4%), including

diarrhoea and constipation,

and respiratory (0.7%) (e.g. bronchitis,

bronchiolitis). Ten infants

(0.5%) required hospital

admission for septicaemia

(n=1), dehydration (n=2), hernia

(n=1) and

NR NR NR

Unclear – (patients

were included into

the study over a period

of two weeks. And

"patients were visited

on two occasions: at

the time of inclusion and

after four weeks"

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Length of treatment

bronchitis or bronchiolitis

(n=2)

Keefe 2006 [15]

"REST Routine for Infant Irritability" - an individualised

intervention programme 4 week programme NR

"Standard well-child care"

4 week programme

NR

4 weeks treatment over am 8 week study

period

Kianifar 2014 [16]

Protexom Restore; a mixture of seven probiotic

strains (Lactobacillus casei, L. rhamnosus, S.

thermophiles, Bifidobacterium breve, L.

acidophilus, B. infantis, L. bulgaricus) plus

fructooligosacharide

Parents advised to mix treatment or

placebo sachet with breast milk daily for a

period of 30 days

None

Placebo - matched for

size, volume, shape and

manufactured by the same company

Same as treatment - daily for 30

days

None 30 days

Landgren 2010 [2]

Acupuncture

Structured programme with six visits to the

clinic, including acupuncture

NR Control group

Structured programme

with six visits to the clinic,

without acupuncture

NR Six weeks

Mi 2015 [17]

L. reuteri DSM 17938 daily None Placebo daily None 28 days

Miller 2012 [34]

Chiropractic treatment Varied NR NA NA NA Varied

Moravej 2010 [18]

Mothers of infants in the case group were asked to avoid cow and goat milk as well as dairy products for 2 weeks and were prescribed calcium supplements, and

instructed to take a calcium-rich diet.

NA NR No change in

the mother's diet (regular diet)

NA NR 2 weeks

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Length of treatment

Oshikoya 2009 [35]

353 infants were treated using self-medication:

Herbal medicines (183/51.8%);

Nospamin (125/35.4%); Gripe water (106/30%); Bonababe (19/5.4%);

Piccan (7/2%); Kidcare (4/1.1%);

Teething powder (4/1.1%); Gbomoro (3/0.8%);

Paracetamol (3/0.8%); Ascorbic acid (3/0.8%);

Ampicillin/cloxacillin (3/0.8%)

120 (31.8%) used

chiropractic intervention (e.g. massage)

133 (35.2%) used

psychosocial interventions

157 mothers sought hospital-based intervention -

59.3% of infants were prescribed medicines

(Nospamin: 49.5%; Gripe water: 43%; Piccan: 12.9%;

Erythromycin: 10.8%; Abidec: 9.7%); 24.8% of

mothers received counselling

NA NA NA NA NA NA

Reinthal 2008 [19]

Children were breastfed prior to treatment. Light

needling (minimal

Light needling session every two weeks

NR Received same

procedure by the parents and

Every two weeks

NR 2 weeks (4 treatments

total)

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Length of treatment

acupuncture) by penetrating the skin with a 0.2mm sterile

disposable needle at acupuncture site LI4,

located between the thumb and forefinger, deep enough

to reach the dorsal interosseous muscle, on both left and right hands. The needle was briefly

rotated for a few seconds (less than 5), left in place for

another period of second and then removed

caring by the investigator

except for light needling

Salisbury 2012 [20]

Therapy sessions in which a behavioural paediatrician

and mental health clinician worked together to assess potential causes of infant

crying and to address emotional and psychological needs of parents. Clinicians

worked with patients to develop and individualised family treatment plan which

families took home

Therapy at baseline, 2- and 6-week follow

up NR

Standard care from own

healthcare provider

Standard care- clinic

appointments at times

individualised to families

NR 10 weeks

Savino 2015 [21]

L. reuteri DSM 17938 + vitamin D3

108 cfu + 400 UI NR vitamin D3 400 UI daily NR 12 weeks

Savino 2010 [22]

A suspension of freeze-dried lactobacillus reuteri in a mixture of sunflower oil

and medium-chain triglyceride oil supplied in a 5-mL dark bottle fitted with a

dropper cap.

5 drops, once a day, 30 minutes before the

feed in the morning

Rhinitis (n=1) (deemed

unrelated to study product).

Placebo - identical in

appearance and taste but without the live bacteria.

5 drops, once a day, 30 minutes

before the feed in the morning

Eczema (n=1), fever (n=1), otalgy

(n=1), gastroesophageal

reflux (n =1).

21 days

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Length of treatment

Savino 2006 [23]

New formula: formula contains partially hydrolysed whey proteins, a mixture of

OS 0.8 g/100 ml, comprising 90% galacto-OS and 10%

fructo OS low lactose level, modified vegetable oil with 41% of the palmitic acid in the b-position and starch.

The feeding volume was based on a

feeding ad libitum procedure. Feeding

frequency was decided by parents

NR Standard formula +

simethicone

simethicone (6 mg/kg

twice a day) NR 14 days

Savino 2007 [24]

Probiotic L reuteri (American Type Culture Collection strain 55730)

108 cfu in 5 drops of a commercially available oil

suspension, 30 minutes after feeding,

once per day

None simethicone

60 mg/day in 15 drops

twice per day of a

commercially available

solution, after feeding

None 28

days

Skjeie 2013 [25]

Acupuncture - The GP made a mark, 3 mm in

diameter, at the point ST36 bilaterally on all children, to hide the insertion mark. In the intervention group, an ethylene-oxidised sterile

Seirin acupuncture-needle (0.20 X15mm) was inserted

at the acupuncture point ST36. The point was needled bilaterally to

approximately 12 mm depth. The two needles were left

inserted without manipulation for 30

seconds. The needles were withdrawn and the insertion area was was covered with

The same procedure was performed on

days 4 and 5.


An identical procedure,

except for the needle

insertions

The same procedure

was performed on days 4 and 5.


5 days

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Length of treatment

an adhesive dressing.

Sung 2014 [26]

L reuteri DSM 17938 (0.2×10

8 cfu per drop) in an

oil suspension

Five drops orally given once daily

None

Maltodextrin in the same oil

suspension with the same

appearance, colour and taste as the treatment,

identically packaged and

stored.

NR None One month

Szajewska 2013 [27]

L reuteri DSM 17938, administered orally,

or placebo.

108 cfu. 5 drops, 1

time daily None

Identical formulation in all respects except

that the live probiotic

bacteria were excluded

5 drops, 1 time daily

None 21 days

Key: cfu – colony forming units; NR: Not reported; NA: Not Applicable; GP: General Practitioner

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Table 1.5: Cost of illness studies: details of evidence and results

Study ID Method of estimating COI Components

included Evidence sources

Currency and year

Results Limitations

Park 2015 [30]

Measurement of hospitalisations from the Kids Inpatient Sample Database

(KIDS) covering 44 US states with calculation of mean cost

per stay

Hospitalisations


hospital charges

2009 US$

The rate of discharge for those under 12 months was 0.8 per 10,000 discharges for constipation, 1.0 per 10,000 discharges for

abdominal pain and 0.1 per 10,000 discharges for dyspepsia. Average cost per hospitalization

for FGID increased from $6115 (1997) to $18058 (2009); Costs for patients diagnosed with abdominal pain increased (on average)

from $3558 to $13331; Length of hospital stay increased from 1.7 (1997) to 2.0 (2009) days; Costs for IBS increased from $5278 (1997) to $18853 (2009); Costs for abdominal migraine

increased from $4876 (1997) to $15139 (2009); Costs for dyspepsia increased from $12674 to $35898 (2009); Costs for fecal incontinence

increased from $6609 to $13252 (2009); Costs for constipation increased from $3693 to

$11873. The costs for all hosptializations of paediatric FGIDs increased significantly from

1997 to 2009 .

Costs are for all children under 18

Sethi 2014 [29]

Measurement of inpatient stays from national inpatient

sample (NIS) database (approx 20% sample of USA

inpatient stays) with calculation of mean cost per

stay

Inpatient stays


hospital charges

2010 US$

Mean costs per stay were $17,518 in 2010 but this was for all patients (children and adults).

Total admissions for children under 12 months from the NIS database was 499 in 2010



adults.

Sommers 2014 [28]

Measurement of ED visits from Nationwide Emergency

Department Sample (NEDS) database (approx 20% sample

of USA ED Visits) with calculation of mean cost per

visit

ED visits ED database and hospital

charges 2011 US$

Mean costs per ED visit were $2,470 in 2011 but this was for all patients (children and

adults). Total ED visits in 2011 from the NEDS database was 50,934 for children under 12

months



adults.

Key: COI – cost of ilness; ED – emergency department; FGID - Functional gastrointestinal disorders.

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1.5 RISK OF BIAS ASSESSMENT

The risk of bias (quality) of the 26 included RCTs was generally unclear (Table 1.6). Five

trials had a high risk of bias [13, 19-21, 24]; six trials had an unclear risk of bias [5, 6, 11, 12,

15, 18]; seven trials had a low/unclear risk of bias [2, 4, 8, 14, 16, 17, 25]; eight trials had a

low risk of bias [3, 7, 9, 10, 22, 23, 26, 27].

The quality of the 5 eligible observational studies was generally poor. Further details of the

quality assessment for the observational studies are reported in Table 1.7.

The quality of the cost of illness studies was generally good being based upon database

analysis and providing reasonable samples of the entire population. However, the studies

were focussed on just one aspect of the cost of illness and the costs applied were not

specific to infants under 12 months. The risk of bias assessment of the three COI studies is

reported in Table 1.8.

1.6 CONCLUSIONS

The systematic review identified a range of treatments that have been or are used for infant

FGID from countries across all continents. It also identified three studies from the USA that

estimated an aspect of the COI of FGID. However, the detail contained in all identified

studies was insufficient to generate a unified COI calculation for a single country. In

particular, there was no evidence found on the scale of use of different treatments and

interventions for infant FGID and colic outside of the use of hospital care in the USA,

predominantly for constipation.

The information identified in the systematic review, whilst not directly estimating a COI of

infant FGID in any particular country, provides useful background in constructing a de novo

calculation.

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Table 1.6: Systematic review: Risk of bias assessment of RCTs

Study ID

Was the allocation sequence

adequately generated?

Was allocation adequately concealed?

Was knowledge of the allocated interventions adequately prevented during the

study?

Were incomplete

outcome data adequately addressed?

Are reports of the study free of suggestion of selective

outcome reporting?

Was the study apparently free

of other problems that

could put it at a high risk of

bias?

Overall risk of bias

Akcam 2006 [3] Yes Yes Yes No Unclear Yes Low

Alves 2012 [4] Yes Unclear Yes Yes Unclear Unclear Low/Unclear

Arikan 2008 [5] Unclear Unclear No Yes Unclear Unclear Unclear

Berseth 2009 [6] Unclear Unclear Unclear Yes Unclear Yes Unclear

Bongers 2007 [7] Yes Yes Yes Unclear Unclear Unclear Low

Browning 2008 [8] Yes Unclear Yes No Unclear Unclear Low/Unclear

Chau 2015 [9] Yes Yes Yes No Unclear Yes Low

Cirgin 2006 [10] Yes Yes Yes No Unclear Yes Low

Coccorullo 2010 [11] Yes Unclear Unclear No Unclear Unclear Unclear

Dupont 2010 [12] Unclear Unclear Unclear No Unclear Yes Unclear

Hayden 2006 [13] Yes Unclear No No Unclear Unclear High

Hill 2005 [14] Yes Unclear Yes Yes Unclear Yes Low/Unclear

Keefe 2006 [15] Yes Unclear Unclear Yes Unclear Yes Unclear

Kianifar 2014 [16] Yes Unclear Yes Yes Yes Yes Low/Unclear

Landgren 2010 [2] Yes Unclear Yes Yes Yes Yes Low/Unclear

Mi 2015 [17] Yes Unclear Yes Yes Unclear Yes Low/Unclear

Moravej 2010 [18] Unclear Unclear Yes No Unclear Unclear Unclear

Reinthal 2008 [19] No Unclear Unclear NA Yes Yes High

Salisbury 2012 [20] Unclear Unclear No Unclear Yes No High

Savino 2015 [21] Yes No Unclear Yes Yes Yes High

Savino 2010 [22] Yes Yes Yes No Yes Yes Low

Savino 2006 [23] Yes Yes Yes No Unclear Yes Low

Savino 2007 [24] Yes No No No Yes Yes High

Skjeie 2013 [25] Unclear Yes Yes No Unclear Yes Low/Unclear

Sung 2014 [26] Yes Yes Yes No Yes Yes Low

Szajewska 2013 [27] Yes Yes Yes Yes Yes Yes Low

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Table 1.7: Systematic review: Risk of bias assessment of observational studies

Cohort study

Is there sufficient description of the groups and the distribution of prognostic factors?

Is the group(s) assembled at a similar point in their disease progression?

Is the intervention / treatment reliably ascertained?

Were the groups comparable on all important confounding factors?

Was there adequate adjustment for the effects of these confounding variables?

Was a dose-response relationship between intervention and outcome demonstrated?

Was outcome assessment blind to exposure status?

Was follow up long enough for the outcomes to occur?

What proportion of the cohort was followed up?

Were drop-out rates and reasons for drop-out similar across intervention and unexposed groups?

Miller 2012 [34] Yes No No No Yes Not Applicable No

Not Applicable

Not Applicable

No

Overall quality: Poor Precludes any association of changes seen with treatment as all the effects observed may be a consequence of effect upon the mothers reporting rather than direct effects on the infant. Subject to sampling bias, limited to one teaching clinic.

Case series

Is the study based on a representative sample selected from a relevant population?

Are the criteria for inclusion explicit?

Did all individuals enter the survey at a similar point in their disease progression?

Was follow-up long enough for important events to occur?

Were outcomes assessed using objective criteria or was blinding used?

If comparisons of sub-series are being made, was there sufficient description of the series and the distribution of prognostic factors?

Aviner 2010 [31] Yes Yes Yes NA (retrospective) Yes NA

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Cross sectional

Representativeness of the sample

Sample size: a) Justified satisfactory. * b) Not justified

Non-respondents:

Ascertainment of the exposure (risk factor)

Comparability: The subjects in different outcome groups are comparable based on the study design or analysis. Confounding factors are controlled.

Assessment of the outcom

Statistical test of the outcome.

Ciftci 2007 [32] Truly representative of the average in the

target population Satisfactory

No description of the characteristics of non-responders

Non-validated measurement tool, but the tool is available or

described

Only one group Self-report Statistical analysis

described


Non-random sample Not justified Only one group No description of measurement tool



described

Oshikoya 2009 [35]

Truly representative of the average in the

target population Not justified Only one group

No description of validation tool



described

Table 1.8: Systematic review: Quality assessment of COI studies

Study ID


Were the quality of the data used assessed and described?

Were data sources and dates clearly reported?

Were data gaps described?

Were data extrapolations reasonable?

Were reasonable methods employed to avoid double counting?

Were the calculations of cost clearly described?

Were the methods used to handle uncertainty appropriate?

Have the researchers offered assessments of the limitations of the study approach?


Park 2015[30] Yes No Yes No NA Unclear Unclear Unclear Yes Yes

Sethi 2014[29] Yes Yes Yes

Yes - only primary



undertaken Yes Yes

Sommers 2015[28] Yes Yes Yes

Yes - only primary



undertaken Yes Yes

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APPENDIX A

Search Strategies for the Systematic Review

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Appendix A i

A.1: Source: MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid

MEDLINE(R) 1946 to Present.

Interface: Ovid SP

Coverage: 1946 to present. Updated daily.



Search strategy:

Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid

MEDLINE(R) <1946 to Present>

Search Strategy:

--------------------------------------------------------------------------------


2 (costing adj3 (illness$ or disease$ or sickness$)).ti,ab,kf. (39)

3 (burden adj3 (illness$ or disease$ or sickness$)).ti,ab,kf. (18484)


caregiver$ or care-giver$)).ti,ab,kf. (5253)

5 ((economic or human$) adj3 consequence$1).ti,ab,kf. (4627)

6 "costs and cost analysis"/ or cost-benefit analysis/ (105504)

7 exp health care costs/ (50444)

8 (cost or costs or economic evaluation or pharmacoeconomic).ti,ab,kf. (367790)

9 (resource$1 adj4 use$1).ti,ab,kf. (20035)

10 (resource$1 adj4 usage).ti,ab,kf. (402)

11 (resource$1 adj4 utili$).ti,ab,kf. (10141)


emergency room or rescue).ti,ab,kf. (495389)

13 quality-adjusted life years/ or "quality of life"/ (137895)

14 (quality adjusted life or qol).ti,ab,kf. (30636)

15 (qaly$ or qald$ or qale$ or qtime$).ti,ab,kf. (6312)

16 (sf36 or sf 36 or sf thirtysix or sf thirty six).ti,ab,kf. (15336)

17 (sf6 or sf 6 or short form or shortform or sf six or sfsix).ti,ab,kf. (21906)

18 (sf12 or sf 12 or sf twelve or sftwelve).ti,ab,kf. (2821)

19 (sf16 or sf 16 or sf sixteen or sfsixteen).ti,ab,kf. (19)

20 (sf20 or sf 20 or sf twenty or sftwenty).ti,ab,kf. (310)

21 (euroqol or eq5d or eq 5d).ti,ab,kf. (5304)

22 (hql or hqol or hrqol or hrql or hr ql).ti,ab,kf. (12031)

23 (hye or hyes).ti,ab,kf. (57)

24 health$1 year$1 equivalent$1.ti,ab,kf. (40)

25 (hui or hui1 or hui2 or hui3).ti,ab,kf. (1051)

26 disutili$.ti,ab,kf. (273)

27 (quality adj3 (wellbeing or well being)).ti,ab,kf. (1606)

28 qwb.ti,ab,kf. (185)

29 (willingness adj3 pay).ti,ab,kf. (2954)

30 standard gamble$.ti,ab,kf. (712)

31 (time trade off$1 or time tradeoff$1 or tto or timetradeoff).ti,ab,kf. (1349)


state$1)).ti,ab,kf. (305820)

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33 (preference$ adj3 (patient$1 or public or valu$ or measur$)).ti,ab,kf. (13395)

34 ((quality adj3 life) or qol).ti,ab,kf. (180949)

35 (index adj3 wellbeing).ti,ab,kf. (90)

36 (multiattribute$ health or multi attribute$ health).ti,ab,kf. (54)


attribute$ analys$).ti,ab,kf. (10)

38 (multiattribute$ utilit$ or multi attribute$ utilit$).ti,ab,kf. (214)

39 (utilit$ adj3 (valu$ or measur$ or health or life or estimat$ or elicit$ or disease)).ti,ab,kf.

(7231)

40 (euro qual or euroqual).ti,ab,kf. (15)

41 (visual analog$ or vas).ti,ab,kf. (52444)

42 (prom or proms or patient reported outcome$1 or pro or pros).ti,ab,kf. (139404)

43 functional assessment.ti,ab,kf. (6663)

44 (symptom$1 adj4 (score$1 or scale$ or instrument$1 or measur$)).ti,ab,kf. (42712)

45 exp patient satisfaction/ (67136)

46 (satisfaction or dissatisf$ or unsatisf$).ti,ab,kf. (115925)

47 (anxiety or depression or anxious or depressed).ti,ab,kf. (373073)

48 exp emotions/ (184194)

49 exp fatigue/ or absenteeism/ or presenteeism/ (30147)

50 stress,psychological/ (93810)


or (severity adj2 dyspepsia assessment) or SODA).ti,ab,kf. (3661)


(concern$1 or perception$1 or view$1 or worry or worrie$1)).ti,ab,kf. or exp parents/px

(48279)

53 or/1-52 (2181547)

54 (colic/ or exp diarrhea/ or colonic diseases, functional/ or exp abdominal pain/) and

(exp infant/ or child, preschool/) (18890)

55 diarrhea, infantile/ (6791)

56 gastrointestinal diseases/ and pain/ and (exp infant/ or child, preschool/) (52)

57 (constipation/ or vomiting/) and (exp infant/ or child, preschool/) (5457)



constipated or regurgitat$ or spitting or spit)).ti,ab,kf. (2580)



bowel movement$1)).ti,ab,kf. (2979)


new born or toddler$1 or child or children or pediatric or paediatric)).ti,ab,kf. (111)


born or toddler$1 or child or children or pediatric or paediatric)).ti,ab,kf. (1101)


or new born or toddler$1 or child or children or pediatric or paediatric)).ti,ab,kf. (4306)




pediatric or paediatric)).ti,ab,kf. (15466)

64 or/54-63 (39733)

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65 53 and 64 (6472)

66 exp animals/ not humans/ (4171020)

67 (news or comment or editorial or letter or case reports).pt. or case report.ti. (3216568)

68 65 not (66 or 67) (5990)



A.2: Source: Embase

Interface: Ovid SP

Coverage: 1974-13/01/2016



Search strategy:

Database: Embase <1974 to 2016 January 13>

Search Strategy:

--------------------------------------------------------------------------------


2 (costing adj3 (illness$ or disease$ or sickness$)).ti,ab,kw. (60)

3 (burden adj3 (illness$ or disease$ or sickness$)).ti,ab,kw. (27543)


caregiver$ or care-giver$)).ti,ab,kw. (7788)

5 ((economic or human$) adj3 consequence$1).ti,ab,kw. (5927)

6 exp "health care cost"/ (227557)

7 "cost benefit analysis"/ (70174)

8 (cost or costs or economic evaluation or pharmacoeconomic).ti,ab,kw. (492815)

9 (resource$1 adj4 use$1).ti,ab,kw. (27684)

10 (resource$1 adj4 usage).ti,ab,kw. (600)

11 (resource$1 adj4 utili$).ti,ab,kw. (16726)


emergency room or rescue).ti,ab,kw. (759153)

13 quality-adjusted life year/ or "quality of life"/ or gastrointestinal quality of life index/

(316485)

14 (quality adjusted life or qol).ti,ab,kw. (53815)

15 (qaly$ or qald$ or qale$ or qtime$).ti,ab,kw. (11705)

16 (sf36 or sf 36 or sf thirtysix or sf thirty six).ti,ab,kw. (24797)

17 (sf6 or sf 6 or short form or shortform or sf six or sfsix).ti,ab,kw. (28593)

18 (sf12 or sf 12 or sf twelve or sftwelve).ti,ab,kw. (4810)

19 (sf16 or sf 16 or sf sixteen or sfsixteen).ti,ab,kw. (35)

20 (sf20 or sf 20 or sf twenty or sftwenty).ti,ab,kw. (298)

21 (euroqol or eq5d or eq 5d).ti,ab,kw. (9656)

22 (hql or hqol or hrqol or hrql or hr ql).ti,ab,kw. (18786)

23 (hye or hyes).ti,ab,kw. (102)

24 health$1 year$1 equivalent$1.ti,ab,kw. (42)

25 (hui or hui1 or hui2 or hui3).ti,ab,kw. (1520)

26 disutili$.ti,ab,kw. (500)

27 (quality adj3 (wellbeing or well being)).ti,ab,kw. (2241)

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28 qwb.ti,ab,kw. (218)

29 (willingness adj3 pay).ti,ab,kw. (4665)

30 standard gamble$.ti,ab,kw. (887)

31 (time trade off$1 or time tradeoff$1 or tto or timetradeoff).ti,ab,kw. (1892)


state$1)).ti,ab,kw. (381531)

33 (preference$ adj3 (patient$1 or public or valu$ or measur$)).ti,ab,kw. (19215)

34 ((quality adj3 life) or qol).ti,ab,kw. (283686)

35 (index adj3 wellbeing).ti,ab,kw. (137)

36 (multiattribute$ health or multi attribute$ health).ti,ab,kw. (67)


attribute$ analys$).ti,ab,kw. (19)

38 (multiattribute$ utilit$ or multi attribute$ utilit$).ti,ab,kw. (277)

39 (utilit$ adj3 (valu$ or measur$ or health or life or estimat$ or elicit$ or

disease)).ti,ab,kw. (11011)

40 (euro qual or euroqual).ti,ab,kw. (24)

41 (visual analog$ or vas).ti,ab,kw. (76768)

42 (prom or proms or patient reported outcome$1 or pro or pros).ti,ab,kw. (203085)

43 functional assessment.ti,ab,kw. (10049)

44 (symptom$1 adj4 (score$1 or scale$ or instrument$1 or measur$)).ti,ab,kw. (64027)

45 patient preference/ or patient satisfaction/ (105494)

46 (satisfaction or dissatisf$ or unsatisf$).ti,ab,kw. (157169)

47 (anxiety or depression or anxious or depressed).ti,ab,kw. (505966)

48 exp emotion/ (420006)

49 fatigue/ or exhaustion/ or lassitude/ (138163)

50 absenteeism/ or job performance/ or productivity/ (54173)

51 caregiver burden/ or emotional stress/ or mental stress/ or maternal stress/ or parental

stress/ (84316)


or (severity adj2 dyspepsia assessment) or SODA).ti,ab,kw. (4773)


(concern$1 or perception$1 or view$1 or worry or worrie$1)).ti,ab,kw. (21366)

54 or/1-53 (3222665)

55 infantile colic/ or newborn vomiting/ or infantile diarrhea/ (3950)

56 (colic/ or diarrhea/ or chronic diarrhea/ or colon disease/ or intestine function disorder/

or exp abdominal pain/ or irritable colon/ or defecation disorder/) and (exp infant/ or

preschool child/) (22242)

57 (gastrointestinal pain/ or gastrointestinal symptom/) and (exp infant/ or preschool child/)

(2097)

58 (exp constipation/ or vomiting/) and (exp infant/ or preschool child/) (14916)



constipated or regurgitat$ or spitting or spit)).ti,ab,kw. (3546)



bowel movement$1)).ti,ab,kw. (3761)


new born or toddler$1 or child or children or pediatric or paediatric)).ti,ab,kw. (222)

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born or toddler$1 or child or children or pediatric or paediatric)).ti,ab,kw. (1426)


or new born or toddler$1 or child or children or pediatric or paediatric)).ti,ab,kw. (5608)




pediatric or paediatric)).ti,ab,kw. (17369)

65 or/55-64 (58135)

66 54 and 65 (11408)

67 (editorial or letter or note).pt. (2039212)

68 case report/ or case report.ti. (2087284)

69 (animal/ or animal experiment/ or animal model/ or animal tissue/ or nonhuman/) not

exp human/ (5260862)

70 66 not (67 or 68 or 69) (9940)


A.3: Source: PubMed

Interface: http://www.ncbi.nlm.nih.gov/pubmed/

Coverage: 1946-current. Updated daily



Search strategy:

Note – PubMed muddles the lines in the search history, and therefore the order of the

search lines is altered from the original MEDLINE strategy and is not especially logical.

#87 Search (#83 NOT #84) Filters: Publication date from 2005/01/01 to 2016/12/31;

English 1395

#86 Search (#83 NOT #84) Filters: Publication date from 2005/01/01 to 2016/12/31

1442

#85 Search (#83 NOT #84) 1569

#84 Search MEDLINE[sb] 22893753

#83 Search (#80 NOT (#81 OR #82)) 15594

#82 Search animals[mh] NOT humans[mh:noexp] 4167646

#81 Search news[pt] OR editorial[pt] OR letter[pt] OR comment[pt] OR case reports[pt]

OR case report[ti] 3223352

#80 Search (#79 AND #62) 17287

#79 Search (#63 OR #64 OR #65 OR #66 OR #67 OR #68 OR #69 OR #70 OR #71 OR

#72 OR #73 OR #74 OR #75 OR #76 OR #77 OR #78) 70185



OR pediatric[ot] OR paediatric[ot]) AND (dyschezia[ot] OR colonic inertia[ot] OR diarrhea[ot]

OR diarrhea[ot] OR cramp*[ot] OR reflux[ot] OR functional abdominal pain[ot] OR bowel

symptom*[ot] OR irritable bowel[ot] OR IBS[ot]) 2364



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children[tiab] OR pediatric[tiab] OR paediatric[tiab]) AND (dyschezia[tiab] OR colonic

inertia[tiab] OR diarrhea[tiab] OR diarrhea[tiab] OR cramp*[tiab] OR reflux[tiab] OR

functional abdominal pain[tiab] OR bowel symptom*[tiab] OR irritable bowel[tiab] OR

IBS[tiab]) 26271



OR pediatric[ot] OR paediatric[ot]) AND gastrointestinal[ot] 807



children[tiab] OR pediatric[tiab] OR paediatric[tiab]) AND gastrointestinal[tiab] 17631



OR pediatric[ot] OR paediatric[ot]) AND crying[ot] 59



children[tiab] OR pediatric[tiab] OR paediatric[tiab]) AND crying[tiab] 2477



OR pediatric[ot] OR paediatric[ot]) AND (fgid[ot] OR fgids[ot]) 2



children[tiab] OR pediatric[tiab] OR paediatric[tiab]) AND (fgid[tiab] OR fgids[tiab]) 115



OR pediatric[ot] OR paediatric[ot]) AND (colicky[ot] OR defecat*[ot] OR stool*[ot] OR bowel

movement*[ot]) 53



children[tiab] OR pediatric[tiab] OR paediatric[tiab]) AND (colicky[tiab] OR defecat*[tiab] OR

stool*[tiab] OR bowel movement*[tiab]) 11169



OR pediatric[ot] OR paediatric[ot]) AND (colic[ot] OR constipation[ot] OR constipated[ot] OR

regurgitat*[ot] OR spitting[ot] OR spit[ot]) 244



children[tiab] OR pediatric[tiab] OR paediatric[tiab]) AND (colic[tiab] OR constipation[tiab]

OR constipated[tiab] OR regurgitat*[tiab] OR spitting[tiab] OR spit[tiab]) 7520

#66 Search (Constipation[mh:noexp] OR vomiting[mh:noexp]) AND (infant[mh] OR child,

preschool[mh:noexp]) 5459

#65 Search gastrointestinal diseases[mh:noexp] AND pain[mh:noexp] AND (infant[mh]

OR child, preschool[mh:noexp]) 52

#64 Search diarrhea, infantile[mh:noexp] 6788

#63 Search (colic[mh:noexp] OR diarrhea[mh] OR colonic diseases, functional[mh:noexp]

OR abdominal pain[mh]) AND (infant[mh] OR child, preschool[mh:noexp]) 18868

#62 Search (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11



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OR #56 OR #57 OR #58 OR #59 OR #60 OR #61) 3966477

#61 Search euroqual[tiab] OR euro qual[tiab] OR euroqual[ot] OR euro qual[ot] 16

#60 Search ((parent*[tiab] OR family[tiab] OR families[tiab] OR mother*[tiab] OR

father*[tiab] OR caregiver*[tiab] OR care-giver*[tiab]) AND (concern*[tiab] OR

perception*[tiab] OR view*[tiab] OR worry[tiab] OR worrie*[tiab])) OR

"Parents/psychology"[Mesh] 97038

#59 Search (parent*[ot] OR family[ot] OR families[ot] OR mother*[ot] OR father*[ot] OR

caregiver*[ot] OR care-giver*[ot]) AND (concern*[ot] OR perception*[ot] OR view*[ot] OR

worry[ot] OR worrie*[ot]) 522

#58 Search symptom*[ot] AND (score*[ot] OR scale*[ot] OR instrument*[ot] OR

measur*[ot]) 746

#57 Search satisfaction[tiab] OR dissatisf*[tiab] OR unsatisf*[tiab] OR satisfaction[ot] OR

dissatisf*[ot] OR unsatisf*[ot] 119170

#56 Search anxiety[tiab] OR depression[tiab] OR anxious[tiab] OR depressed[tiab] OR

anxiety[ot] OR depression[ot] OR anxious[ot] OR depressed[ot] 381561

#55 Search emotions[mh] 184091

#54 Search stress,psychological[mh] 99836

#53 Search fatigue[mh] OR absenteeism[mh:noexp] OR presenteeism[mh:noexp]

30106

#52 Search (gastrointestinal[tiab] AND rating scale[tiab]) OR (gastrointestinal[ot] AND

rating scale[ot]) 603

#51 Search GSRS[tiab] OR GIQLI[tiab] OR SODA[tiab] OR GSRS[ot] OR GIQLI[ot] OR

SODA[ot] 3609

#50 Search gastrointestinal[tiab] AND quality[tiab] AND index[tiab] 834

#49 Search severity[tiab] AND dyspepsia[tiab] AND assessment[tiab] 118

#48 Search utilit*[tiab] AND (valu*[tiab] OR measur*[tiab] OR health[tiab] OR life[tiab] OR

estimat*[tiab] OR elicit*[tiab] OR disease[tiab]) 78309

#47 Search utilit*[ot] AND (valu*[ot] OR measur*[ot] OR health[ot] OR life[ot] OR

estimat*[ot] OR elicit*[ot] OR disease[ot]) 289

#46 Search visual analog*[tiab] OR vas[tiab] OR visual analog*[ot] OR vas[ot] 53203

#45 Search prom[ot] OR proms[ot] OR patient reported outcome*[ot] OR pro[ot] OR

pros[ot] OR prom[tiab] OR proms[tiab] OR patient reported outcome*[tiab] OR pro[tiab] OR

pros[tiab] 143056

#44 Search functional assessment[tiab] OR functional assessment[ot] 6822

#43 Search symptom*[tiab] AND (score*[tiab] OR scale*[tiab] OR instrument*[tiab] OR

measur*[tiab]) 238078

#42 Search patient satisfaction[mh] 67067

#41 Search (valu*[tiab] OR measur*[tiab]) AND (health[tiab] OR outcome*[tiab] OR

effect*[tiab] OR change*[tiab] OR state*[tiab]) 2131060

#40 Search (valu*[ot] OR measur*[ot]) AND (health[ot] OR outcome*[ot] OR effect*[ot] OR

change*[ot] OR state*[ot]) 7042

#39 Search preference*[tiab] AND (patient[tiab] OR patients[tiab] OR public[tiab] OR

valu*[tiab] OR measur*[tiab]) 47688

#38 Search preference*[ot] AND (patient[ot] OR patients[ot] OR public[ot] OR valu*[ot]

OR measur*[ot]) 814

#37 Search (quality[tiab] AND life[tiab]) OR qol[tiab] 204509

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#36 Search (quality[ot] AND life[ot]) OR qol[ot] 9470

#35 Search (index[tiab] AND wellbeing[tiab]) OR (index[ot] AND wellbeing[ot]) 503

#34 Search multiattribute*[tiab] OR multi attribute*[tiab] OR multiattribute*[ot] OR multi

attribute*[ot] 603

#33 Search healthy years equivalent[tiab] OR healthy years equivalent[ot] 23

#32 Search hui[tiab] OR hui1[tiab] OR hui2[tiab] OR hui3[tiab] OR hui[ot] OR hui1[ot] OR

hui2[ot] OR hui3[ot] 1064

#31 Search disutili*[tiab] OR disutili*[ot] 282

#30 Search quality[tiab] AND (wellbeing[tiab] OR well being[tiab]) 14021

#29 Search quality[ot] AND (wellbeing[ot] OR well being[ot]) 157

#28 Search qwb[tiab] OR qwb[ot] 186

#27 Search (willingness[ot] AND pay[ot]) OR (willingness[tiab] AND pay[tiab]) 3312

#26 Search standard gamble[tiab] OR standard gamble[ot] 715

#25 Search time trade off*[ot] OR time tradeoff*[ot] OR tto[ot] OR timetradeoff[ot] OR time

trade off*[tiab] OR time tradeoff*[tiab] OR tto[tiab] OR timetradeoff[tiab] 1385

#24 Search visit[tiab] OR visits[tiab] OR hospitalization*[tiab] OR hospitalisation*[tiab] OR

admission*[tiab] OR admitted[tiab] OR emergency room[tiab] OR rescue[tiab] 505212

#23 Search visit[ot] OR visits[ot] OR hospitalization*[ot] OR hospitalisation*[ot] OR

admission*[ot] OR admitted[ot] OR emergency room[ot] OR rescue[ot] 3817

#22 Search quality-adjusted life years[mh:noexp] or quality of life[mh:noexp] 137823

#21 Search quality adjusted life[tiab] OR qol[tiab] OR quality adjusted life[ot] OR qol[ot]

31622

#20 Search qaly*[tiab] OR qald*[tiab] OR qale*[tiab] OR qtime*[tiab] OR qaly*[ot] OR

qald*[ot] OR qale*[ot] OR qtime*[ot] 6516

#19 Search sf36[ot] OR sf 36[ot] OR sf36[tiab] or sf 36[tiab] 15719

#18 Search sf6[tiab] OR sf 6[tiab] OR short form[tiab] OR shortform[tiab] OR sf six[tiab]

OR sfsix[tiab] 22568

#17 Search hye[tiab] OR hyes[tiab] OR hye[ot] OR hyes[ot] 57

#16 Search hql[tiab] OR hqol[tiab] OR hrqol[tiab] OR hrql[tiab] OR hr ql[tiab] OR hql[ot]

OR hqol[ot] OR hrqol[ot] OR hrql[ot] OR hr ql[ot] 12433

#15 Search euroqol[tiab] OR eq5d[tiab] OR eq 5d[tiab] OR euroqol[ot] OR eq5d[ot] OR eq

5d[ot] 5548

#14 Search sf16[tiab] OR sfsixteen[tiab] OR sf16[ot] OR sfsixteen[ot] OR sf20[tiab] OR

sftwenty[tiab] OR sf20[ot] OR sftwenty[ot] 31

#13 Search sf12[tiab] OR sftwelve[tiab] OR sf12[ot] OR sftwelve[ot] 217

#12 Search sf6[ot] OR sf 6[ot] OR short form[ot] OR shortform[ot] OR sf six[ot] OR

sfsix[ot] 242

#11 Search resource use[tiab] OR resource usage[tiab] OR resource utili*[tiab] OR

resource use[ot] OR resource usage[ot] OR resource utili*[ot] 11538

#10 Search cost[ot] OR costs[ot] OR economic evaluation[ot] OR pharmacoeconomic[ot]

7838

#9 Search cost[tiab] OR costs[tiab] OR economic evaluation[tiab] OR

pharmacoeconomic[tiab] 377282

#8 Search "costs and cost analysis"[mh:noexp] OR cost-benefit analysis[mh:noexp] OR

health care costs[mh] 142701

#7 Search (economic[ot] OR human*[ot]) AND consequence*[ot] 14

#6 Search (economic[tiab] OR human*[tiab]) AND consequence*[tiab] 52990

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#5 Search burden[ot] AND (family[ot] OR families[ot] OR human*[ot] OR mother*[ot] OR

father*[ot] OR parent*[ot] OR caregiver*[ot] OR care-giver*[ot]) 441

#4 Search burden[tiab] AND (family[tiab] OR families[tiab] OR human*[tiab] OR

mother*[tiab] OR father*[tiab] OR parent*[tiab] OR caregiver*[tiab] OR care-giver*[tiab])

27962

#3 Search (costing[ot] OR burden[ot]) AND (illness*[ot] OR disease*[ot] OR

sickness*[ot]) 596

#2 Search (costing[tiab] OR burden[tiab]) AND (illness*[tiab] OR disease*[tiab] OR

sickness*[tiab]) 53782

#1 Search cost of illness[mh:noexp] 19779

A.4: Source: PsycINFO

Interface: Ovid SP

Coverage: 1806-January Week 2 2016



Search strategy:

1 exp "costs and cost analysis"/ (21310)

2 Health Care Economics/ or Pharmacoeconomics/ (810)

3 (costing adj3 (illness$ or disease$ or sickness$)).ti,ab,id. (5)

4 (burden adj3 (illness$ or disease$ or sickness$)).ti,ab,id. (3340)


caregiver$ or care-giver$)).ti,ab,id. (4180)

6 ((economic or human$) adj3 consequence$1).ti,ab,id. (1447)

7 (cost or costs or economic evaluation or pharmacoeconomic).ti,ab,id. (72698)

8 (resource$1 adj4 use$1).ti,ab,id. (7968)

9 (resource$1 adj4 usage).ti,ab,id. (152)

10 (resource$1 adj4 utili$).ti,ab,id. (2629)


emergency room or rescue).ti,ab,id. (95253)

12 "quality of life"/ (30977)

13 (quality adjusted life or qol).ti,ab,id. (7917)

14 (qaly$ or qald$ or qale$ or qtime$).ti,ab,id. (803)

15 (sf36 or sf 36 or sf thirtysix or sf thirty six).ti,ab,id. (3552)

16 (sf6 or sf 6 or short form or shortform or sf six or sfsix).ti,ab,id. (9357)

17 (sf12 or sf 12 or sf twelve or sftwelve).ti,ab,id. (809)

18 (sf16 or sf 16 or sf sixteen or sfsixteen).ti,ab,id. (0)

19 (sf20 or sf 20 or sf twenty or sftwenty).ti,ab,id. (42)

20 (euroqol or eq5d or eq 5d).ti,ab,id. (1292)

21 (hql or hqol or hrqol or hrql or hr ql).ti,ab,id. (3836)

22 (hye or hyes).ti,ab,id. (13)

23 health$1 year$1 equivalent$1.ti,ab,id. (5)

24 (hui or hui1 or hui2 or hui3).ti,ab,id. (438)

25 disutili$.ti,ab,id. (158)

26 (quality adj3 (wellbeing or well being)).ti,ab,id. (1293)

27 qwb.ti,ab,id. (91)

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28 (willingness adj3 pay).ti,ab,id. (1320)

29 standard gamble$.ti,ab,id. (188)

30 (time trade off$1 or time tradeoff$1 or tto or timetradeoff).ti,ab,id. (311)


state$1)).ti,ab,id. (77177)

32 (preference$ adj3 (patient$1 or public or valu$ or measur$)).ti,ab,id. (6173)

33 ((quality adj3 life) or qol).ti,ab,id. (51129)

34 (index adj3 wellbeing).ti,ab,id. (114)

35 (multiattribute$ health or multi attribute$ health).ti,ab,id. (14)


attribute$ analys$).ti,ab,id. (17)

37 (multiattribute$ utilit$ or multi attribute$ utilit$).ti,ab,id. (235)

38 (utilit$ adj3 (valu$ or measur$ or health or life or estimat$ or elicit$ or disease)).ti,ab,id.

(3270)

39 (euro qual or euroqual).ti,ab,id. (4)

40 (visual analog$ or vas).ti,ab,id. (6171)

41 (prom or proms or patient reported outcome$1 or pro or pros).ti,ab,id. (14435)

42 functional assessment.ti,ab,id. (2267)

43 (symptom$1 adj4 (score$1 or scale$ or instrument$1 or measur$)).ti,ab,id. (20641)

44 (satisfaction or dissatisf$ or unsatisf$).ti,ab,id. (98236)

45 (anxiety or depression or anxious or depressed).ti,ab,id. (313389)

46 exp Emotions/ (253774)

47 fatigue/ (7014)

48 employee absenteeism/ (1964)

49 exp job performance/ (17969)

50 psychological stress/ (7972)


or (severity adj2 dyspepsia assessment) or SODA).ti,ab,id. (656)


(concern$1 or perception$1 or view$1 or worry or worrie$1)).ti,ab,id. (27094)

53 Caregiver Burden/ (4856)

54 or/1-53 (862938)

55 infant vocalization/ (992)


toddler$1 or child or children or pediatric or paediatric).id. or (pediatrics/ or exp infant

development/)) and (colon disorders/ or gastrointestinal disorders/ or constipation/ or

diarrhea/ or irritable bowel syndRome/ or crying/) (1008)


toddler$1 or child or children or pediatric or paediatric) and (colic or constipation or

constipated or regurgitat$ or spitting or spit)).ti,ab,id. (540)


toddler$1 or child or children or pediatric or paediatric) and (colicky or defecat$ or stool$1 or

bowel movement$1)).ti,ab,id. (322)


new born or toddler$1 or child or children or pediatric or paediatric)).ti,ab,id. (16)

60 (crying and (infantile or infant$1 or neonat$ or baby or babies or newborn$1 or new

born or toddler$1 or child or children or pediatric or paediatric)).ti,ab,id. (1789)

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61 (gastrointestinal and (infantile or infant$1 or neonat$ or baby or babies or newborn$1

or new born or toddler$1 or child or children or pediatric or paediatric)).ti,ab,id. (664)


abdominal pain or bowel symptom$1 or irritable bowel or IBS) and (infantile or infant$1 or


pediatric or paediatric)).ti,ab,id. (749)

63 or/55-62 (4627)

64 54 and 63 (1338)



A.5: Source: NHS Economic Evaluation Database (NHS EED)



Search date: 17/01/16 and 03/02/16


Search Name:

Date Run: 17/01/16 18:13:19.750

Description:

ID Search Hits




#3 #1 and #2 238



#6 #5 and #2 0

















#13 #12 or #11 or #10 or #9 or #8 or #7 or #6 or #5 or #4 or #3 3163


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ID Search Hits




#3 #1 and #2 258



#6 #5 and #2 0





















#16 #14 and #15 258



#19 #17 and #18 0









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#29 #28 not #27 3

A.6: Source: Health Technology Assessment Database (HTA Database)


Coverage: Issue 4 of 4 October 2015

Search date: 17/01/16 and 03/02/16


Search strategy:

Search Name:

Date Run: 17/01/16 18:13:19.750

Description:

ID Search Hits




#3 #1 and #2 238



#6 #5 and #2 0















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ID Search Hits




#3 #1 and #2 258



#6 #5 and #2 0





















#16 #14 and #15 258



#19 #17 and #18 0




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#29 #28 not #27 1

A.7: Source: Database of Abstracts of Reviews of Effects (DARE)



Search date: 17/01/16 and 03/03/16


Search strategy:

ID Search Hits




#3 #1 and #2 238



#6 #5 and #2 0















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ID Search Hits




#3 #1 and #2 258



#6 #5 and #2 0





















#16 #14 and #15 258



#19 #17 and #18 0




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#29 #28 not #27 15

A.8: Source: NEXIS UK

Interface: LexisNexis

Coverage: No information provided. Last update 19/01/16



Search strategy:

Search of this database intended to identify commercial/market reports on over the counter

sales of interventions

All searches had the following limits applied: Search Market Insight, 01/01/2005 – 20/01/16.

Search All Countries, All Industries, All 20 sources.

Each search string searched separately and the full text downloaded as a Word document.


toddler* OR child OR children OR pediatric OR paediatric) W/5 (colic OR constipation OR

constipated OR regurgitat? OR spitting OR spit) 62 results


toddler* OR child OR children OR pediatric OR paediatric) W/5 (colicky OR defecat? OR

stool* OR “bowel movement*”) 42 results


toddler* OR child OR children OR pediatric OR paediatric) and (fgid or fgids) 0 results


toddler* OR child OR children OR pediatric OR paediatric) W/5 (crying OR cry). Due to the

excessive volume of irrelevant results returned by this search line, these terms were

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additionally limited to the following industries: Food, Health Care, Marketing & Advertising,

Pharmaceuticals, Retail & Wholesale Trade. 27 results.


toddler* OR child OR children OR pediatric OR paediatric) W/5 gastrointestinal 146 results


toddler* OR child OR children OR pediatric OR paediatric) W/5 (dyschezia OR “colonic

inertia” OR diarrhea OR diarrhoea OR cramp? OR reflux OR “functional abdominal pain” OR

“bowel symptom*” OR “irritable bowel” OR IBS) Due to the excessive volume of irrelevant

results returned by this search line, these terms were additionally limited to the following

industries: Food, Health Care, Marketing & Advertising, Pharmaceuticals, Retail &

Wholesale Trade. 251 results.

A.9: Source: CEA Registry

Interface:https://research.tufts-

nemc.org/cear4/SearchingtheCEARegistry/SearchtheCEARegistry.aspx




Search strategy:

Database only supports searching single terms – following used 1 at a time

No export options available. Information specialist added potentially relevant records ONLY

to EndNote by hand. Duplicate records not added.

Colic 3 records/0 potentially relevant

Colicky 0 records

Constipation 5 records/0 potentially relevant

Constipated 1 record/0 potentially relevant

Regurgitation 5 records/0 potentially relevant

Regurgitate 0 records

Regurgitates 0 records

Spitting 0 records

Spits 0 records [NB spit could not be used as a search term as it retrieved over 900 records,

all of the first 5 pages were irrelevant suggesting it is overly sensitive]

Defecation 0 records

Defecate 0 records

Defecated 0 records

Stool 3 records/0 potentially relevant

Stooling 0 records

Stools 0 records

Bowel 29 records/0 potentially relevant

IBS 14 records/0 potentially relevant

FGID 0 records

FGIDS 0 records

Cry 11 records/0 potentially relevant

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Crying 0 records

Gastrointestinal 65 records/0 potentially relevant

Dyschezia 0 records

Colon 78 records/0 potentially relevant

Colonic 11 records/0 potentially relevant



Cramp 2 records/ 0 potentially relevant

Cramps 0 records

Cramping 0 records

Reflux 27 records/0 potentially relevant

A.10: Source: NHS Evidence Search

Interface: http://www.evidence.nhs.uk/




Search strategy:

Note: NHS Evidence is not intended for systematic or structured searches and it does not

have the functionality to support this. The search was translated pragmatically in order to

allow it to be used in NHS Evidence, prioritizing the most specific search terms.

(infantile OR infant* OR baby OR babies OR neonat* OR newborn* OR "new born*" OR

toddler* OR child OR children OR pediatric OR paediatric) AND (fgid or fgids or "functional

gastrointestinal disorder*") 22 records.


toddler* OR child OR children OR pediatric OR paediatric) AND (colic OR colicky) In order to

manage the search volumes the results were filtered by publication type: primary research,

systematic reviews, ongoing research and health technology assessment. 120 records.


toddler* OR child OR children OR pediatric OR paediatric) AND (“excessive crying” OR

“inconsolable crying”) In order to manage the search volumes the results were filtered by

publication type: primary research, systematic reviews, ongoing research and health

technology assessment. 16 records.

(infantile OR infant* OR baby OR babies OR neonat* OR newborn* OR new born* OR

toddler* OR child OR children OR pediatric OR paediatric) AND (regurgitat* OR spit OR

spitting) In order to manage the search volumes the results were filtered by publication type:

primary research, systematic reviews, ongoing research and health technology assessment.

147 records.

All records rapidly assessed by information specialist – 38 potentially relevant records cut

and pasted into Word document. 16 of these had not been previously identified by other

search resources and so were added to EndNote.

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A.11: Source: REPEC

Interface: IDEAS https://ideas.repec.org




Search strategy:

Each search line run individually


child | children | pediatric | paediatric) + (colic | colicky) 1 record


child | children | pediatric | paediatric) + (regurgitat* | spit | spitting) 0 records

fgid | fgids 0 records


child | children | pediatric | paediatric) + (cry OR crying) 24 records


child | children | pediatric | paediatric) + (constipation | constipated) 4 records


child | children | pediatric | paediatric) + (defecat* | stool* | “bowel movement” | "bowel

movements" | gastrointestinal) 22 records


child | children | pediatric | paediatric) + (dyschezia | “colonic inertia” | diarrhea | diarrhoea |

cramp* | reflux | “functional abdominal pain”) 129 records


child | children | pediatric | paediatric) + ("bowel symptom" | "bowel symptoms" | IBS |

"irritable bowel") 1 record

All results rapidly assessed in REPEC by the information specialist for relevance. Only

records not previously identified by database searches were added to EndNote. 1

potentially relevant, non duplicate record remained after this process.

A.12: Source: OAISTER

Interface: Worldcat http://oaister.worldcat.org/



Retrieved records:240

Search strategy:

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Note: OAISTER is not intended for systematic or structured searches and it does not have

the functionality to support this. The search was translated pragmatically in order to allow it

to be used in this resource, prioritizing the most specific search terms.

Each search line run individually and the following limits applied: Non juvenile, English

language only, 2005-2016

'kw:(infantile OR infant* OR baby OR babies OR neonat* OR newborn* OR “new born” OR

“new borns” OR toddler* OR child OR children OR pediatric OR paediatric) AND (colic OR

colicky)' 104 records


“new borns” OR toddler* OR child OR children OR pediatric OR paediatric) AND (fgid or

fgids or "functional gastrointestinal disorder" OR “functional gastrointestinal disorders”)’ 47

records


“new borns” OR toddler* OR child OR children OR pediatric OR paediatric) AND

(inconsolab* OR excessiv*) AND (cry OR crying)’ 21 records


“new borns” OR toddler* OR child OR children OR pediatric OR paediatric) AND (regurgitat*

OR spit OR spitting) 68

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A.13: Source: International Society For Pharmacoeconomics and Outcomes

Research (ISPOR ) conference



Search strategy:

Latin America Conference (every 2 years) – 2013 and 2015 – both indexed in Embase – no


Annual European Congress – 2013, 2014, 2015 – all three indexed in Embase – no


Annual International Meeting – 2013, 2014, 2015 - all three indexed in Embase – no


Asia Pacific Conference (every 2 years) – 2014 – not indexed – handsearched

ISPOR 6TH Asia-Pacific Conference 6-9 September 2014. Beijing, China. Abstract book

scanned by eye by an information specialist at

http://www.ispor.org/conferences/beijing0914/ISPOR-6th-Asia-Pacific-Conference-

Research-Abstracts.pdf [Accessed 18th December 2015]. 0 potentially relevant records

identified.

The ISPOR Scientific Presentation Database

[https://www.ispor.org/RESEARCH_STUDY_DIGEST/research_index.asp] was also

browsed on 18/12/13 for presentations catagorised as the disease group:

a) GI Disorders (8 results returned - no potentially relevant records identified);

b) Health – Children (10 results returned - no potentially relevant records identified);

c) Multiple Diseases. (125 results returned – no potentially relevant records identified)

A.14: Source: European Society for Paediatric Gastroenterology, Hepatology and

Nutrition (ESPGHAN) conference



Search strategy:


handsearched.








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ESPGHAN Annual Meeting May 6-9 2015; Amsterdam Abstract book searched online at

http://espghan.org/uploads/media/ESPGHAN_A4_Abstract_2015_v2.pdf



ESPGHAN Annual Meeting June 9-12 2014; Jerusalem Abstract book searched online at

http://journals.lww.com/jpgn/Documents/ESPGHAN%202014%20Abstracts%20-

%20Complete%20abstracts.pdf



ESPGHAN Annual Meeting May 8-11 2013; London Abstract book searched online at




A.15: Source: North American Society for Pediatric Gastroenterology, Hepatology

and Nutrition (NASPGHAN) conference



Search strategy:


handsearched.








NASPGHAN Annual Meeting October 8-11 2015; Washington, DC. Abstract book

searched online at

http://journals.lww.com/jpgn/Documents/Abstracts%20from%202015%20NASPGHAN%20M

eeting%20in%20Washington,%20DC.pdf [Accessed 18th December 2015].

1 abstract selected

NASPGHAN Annual Meeting October 23-26 2014; Atlanta, GA. Abstract book searched

online at http://journals.lww.com/jpgn/Documents/NASPGHAN%202014%20abstracts.pdf

[Accessed 18th December 2015].

1 abstract selected

NASPGHAN Annual Meeting October 10-12 2013; Chicago, IL. Abstract book searched

online at http://journals.lww.com/jpgn/Documents/NASPGHAN2013_Abstract_Book%20-

%20revised%20Sept%2018,%202013.pdf Accessed 18th December 2015].

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http://journals.lww.com/jpgn/Documents/NASPGHAN%202014%20abstracts.pdf






A.16: Source: World Congress of Pediatric Gastroenterology, Hepatology and

Nutrition.



Search strategy:

Last conference held 2012, next in October 2016 so outside scope of search. Not

handsearched.

A.17: Source: American Academy of Pediatrics National Conference



Search strategy:

AAP National Conference October 24-27 2015; Washington, DC. Abstracts searchable

online at: https://aap.confex.com/aap/2015/webprogrampress/start.html

Accessed 3rd February 2015



time:

colic

colicky

cry

cries

crying

constipation

constipated

constipating

reflux

GERD

GORD

regurgitation

gastrointestinal

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gastro-intestinal

fgid

fgids


AAP National Conference October 11-14 2014; San Diego. Abstracts searchable online

at: https://aap.confex.com/aap/2014/webprogrampress/start.html Accessed 3rd February

2015



time:

colic

colicky

cry

cries

crying

constipation

constipated

constipating

reflux

GERD

GORD

regurgitation

regurgitate

gastrointestinal

gastro-intestinal

fgid

fgids

1 potentially relevant abstract identified

AAP National Conference October 26-29 2013; Orlando Abstracts searchable online at:

https://aap.confex.com/aap/2013/webprogram/start.html Accessed 3rd February 2015


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https://aap.confex.com/aap/2013/webprogram/start.html




time:

colic

colicky

cry

cries

crying

constipation

constipated

constipating

reflux

GERD

GORD

regurgitation

regurgitate

gastrointestinal

gastro-intestinal

fgid

fgids


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APPENDIX B

Excluded Studies

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Table B.1: Unobtainable records (1) Record Exclusion reason

Tikochinski Y, Kukliansky I. Examination of the effect of BornFree ActiveFlow baby bottles on infant colic. Gastroenterol Nurs. 2013;36(2):123-7.

Record unobtainable

Table B.2: Excluded records (125) with reasons for exclusion


Ansari H, Ansari Z, Hutson JM, Southwell BR. Potentially avoidable hospitalisation for constipation in Victoria, Australia in 2010-11. BMC Gastroenterol. 2014;14:125.


Ansari H, Ansari Z, Lim T, Hutson JM, Southwell BR. Factors relating to hospitalisation and economic burden of paediatric constipation in the state of Victoria, Australia, 2002-2009. J Paediatr Child Health. 2014;50(12):993-9.


Arumugam J, Sivandam S, Vijayalakshmi AM. The evaluation and management of an incessantly crying infant. SLJCH. 2012;41(4):192-98.

Literature review

Asipu D, Jaffray B. Treatment of severe childhood constipation with restorative proctocolectomy. Arch Dis Child. 2010;95(11):867-70.


Bae SH, Son JS, Lee R. Effect of fluid intake on the outcome of constipation in children: PEG 4000 versus lactulose. Pediatr Int. 2010;52(4):594-7.


Barr RG, Rajabali F, Aragon M, Colbourne M, Brant R. Education about crying in normal infants is associated with a reduction in pediatric emergency room visits for crying complaints. J Dev Behav Pediatr. 2015;36(4):252-7.


Bishop J, Furman M, Thomson M. Omeprazole for gastroesophageal reflux disease in the first 2 years of life: a dose-finding study with dual-channel pH monitoring. J Pediatr Gastroenterol Nutr. 2007;45(1):50-5.



reflux)

Bu LN, Chang MH, Ni YH, Chen HL, Cheng CC. Lactobacillus casei rhamnosus Lcr35 in children with chronic constipation. Pediatr Int. 2007;49(4):485-90.


Burgers R, Bonanno E, Madarena E, Graziano F, Pensabene L, Gardner W, et al. The care of constipated children in primary care in different countries. Acta Paediatr. 2012;101(6):677-80.


Calado CS, Pereira AG, Santos VN, Castro MJ, Maio JF. What brings newborns to the emergency department?: a 1-year study. Pediatr Emerg Care. 2009;25(4):244-8.

Prevalence study

Chao HC, Vandenplas Y. Effect of cereal-thickened formula and upright positioning on regurgitation, gastric emptying, and weight gain in infants with regurgitation. Nutrition. 2007;23(1):23-8.



reflux)

Chellani H, Dabas A, Arya S. Gastro-esophageal reflux: spitting and possetting in a neonate. Indian J Pediatr. 2015;82(1):39-43.

Literature review

Chen SL, Cai SR, Deng L, Zhang XH, Luo TD, Peng JJ, et al. Efficacy and complications of polyethylene glycols for treatment of constipation in children: a meta-analysis (Provisional abstract). DARE. 2014; (2): e65. Available from: http://onlinelibrary.wiley.com/o/cochrane/cldare/articles/DARE-12014063218/frame.html

Literature review

Chitkara DK, Talley NJ, Weaver AL, Katusic SK, De Schepper H, Rucker MJ, et al. Incidence of presentation of common functional gastrointestinal disorders in children from birth to 5 years: a cohort study. Clin Gastroenterol Hepatol. 2007;5(2):186-91.

Prevalence study

Chu H, Zhong L, Li H, Zhang X, Zhang J, Hou X. Epidemiology characteristics of constipation for general population, pediatric population, and elderly

Literature review

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population in china. Gastroenterol Res Pract. 2014;2014:532734.

Chumpitazi CE, Henkel EB, Valdez KL, Chumpitazi BP. Soap Suds Enema are Efficacious and Safe for Treating Fecal Impaction in Children with Abdominal Pain. J Pediatr Gastroenterol Nutr. 2015


Coccorullo P, Quitadamo P, Martinelli M, Staiano A. Novel and alternative therapies for childhood constipation. J Pediatr Gastroenterol Nutr. 2009;48(SUPPL. 2):S104-S06.

Literature review

Cohen Engler A, Hadash A, Shehadeh N, Pillar G. Breastfeeding may improve nocturnal sleep and reduce infantile colic: potential role of breast milk melatonin. Eur J Pediatr. 2012;171(4):729-32.


Collaco JM, Aherrera AD, Au Yeung KJ, Lefton-Greif MA, Hoch J, Skinner ML. Interdisciplinary pediatric aerodigestive care and reduction in health care costs and burden. JAMA Otolaryngol Head Neck Surg. 2015;141(2):101-5.


Cook F, Bayer J, Le HND, Mensah F, Cann W, Hiscock H. Baby Business: a randomised controlled trial of a universal parenting program that aims to prevent early infant sleep and cry problems and associated parental depression. BMC Pediatr. 2012;12:13.


Crotteau CA, Wright ST. What is the best treatment for infants with colic? J Fam Pract. 2006;55(7):634-36.

Literature review

Dattoli E, Tandoi F, Agosti M, Luini C, Meneghin F, Dilillo D, et al. Functional gastrointestinal disorders in infants and neonatal period: Which correlation? [Conference Abstract]. Dig Liver Dis. 2012;44:S264.

Conference abstract

Dehghani SM, Askarian M, Kaffashan HA. Oral domperidone has no additional effect on chronic functional constipation in children: a randomized clinical trial. Indian J Gastroenterol. 2014;33(2):125-30.


Dehghani SM, Erjaee A, Imanieh MH, Haghighat M. Efficacy of the standard quadruple therapy versus triple therapies containing proton pump inhibitor plus amoxicillin and clarithromycin or amoxicillin-clavulanic acid and metronidazole for helicobacter pylori eradication in children. Dig Dis Sci. 2009;54(8):1720-24.


Del Buono R, Wenzl TG, Ball G, Keady S, Thomson M. Effect of Gaviscon Infant on gastro-oesophageal reflux in infants assessed by combined intraluminal impedance/pH. Arch Dis Child. 2005;90(5):460-3.



reflux)

Devitt P, Thornley E, Hinks M. An evaluation of an inter-disciplinary constipation clinic for childhood constipation. J Res Nurs. 2007;12(5):539-47.


Di Mauro A, Riezzo G, Civardi E, Intini C, Corvaglia L, Ballardini E, et al. Act and not react: Prophylactic use of probiotic in colic, regurgitation and functional constipation, clinical and socio-economic impact. Dig Liver Dis. 2013;45:e302.

Conference abstract

Diamanti A, Bracci F, Reale A, Crisogianni M, Pisani M, Castro M. Incidence, clinical presentation, and management of constipation in a pediatric ED. Am J Emerg Med. 2010;28(2):189-94.

Prevalence study

Ditty A, Garg A, Leggett C, Turner S. Are proton pump inhibitors over-prescribed in infants? J Pharm Pract Res. 2014;44(4):220-23.



reflux)

Dupont C, Leluyer B, Maamri N, Morali A, Joye J-P, Fiorini J-M, et al. Double-blind randomized evaluation of clinical and biological tolerance of polyethylene glycol 4000 versus lactulose in constipated children. J Pediatr Gastroenterol Nutr. 2005;41(5):625-33.


Dziechciarz P, Horvath A, Szajewska H. Polyethylene glycol 4000 for treatment of functional constipation in children. J Pediatr Gastroenterol Nutr. 2015;60(1):65-8.


Elitsur Y. The diagnostic yield of upper endoscopy procedures in children- is it cost effective? Curr Gastroenterol Rep. 2014;16(5):385.


European School of Osteopathy. Cranial Osteopathy in Infantile Colic. In: UK Clinical Trials Gateway [internet]. 2013. Available from https://ukctg.nihr.ac.uk/trials/trial-details/trial-details?trialNumber=NCT01942928. Identifier: NCT01942928


Falconer J. Gastro-oesophageal reflux and gastrooesophageal reflux disease in infants and children. J Fam Health Care. 2010;20(5):175-7; quiz 78.


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Fazil M. Prevalence and risk factors for infantile colic in District Mansehra. J Ayub Med Coll Abbottabad. 2011;23(2):115-7.

Prevalence study

Gomes PB, Duarte MA, Melo Mdo C. Comparison of the effectiveness of polyethylene glycol 4000 without electrolytes and magnesium hydroxide in the treatment of chronic functional constipation in children. J Pediatr. 2011;87(1):24-8.


Hays LJ. Impact upon emotional availability: Infant GERD and infant massage therapy. Diss Abstr Int (B). 2015;75(9-B(E)):No Pagination Specified.


Hegar B, Rantos R, Firmansyah A, De Schepper J, Vandenplas Y. Natural evolution of infantile regurgitation versus the efficacy of thickened formula. J Pediatr Gastroenterol Nutr. 2008;47(1):26-30.



reflux)

Howard CR, Lanphear N, Lanphear BP, Eberly S, Lawrence RA. Parental responses to infant crying and colic: the effect on breastfeeding duration. Breastfeed Med. 2006;1(3):146-55.

Ineligible outcomes

Hua S, Peters RL, Allen KJ, Dharmage SC, Tang ML, Wake M, et al. Medical intervention in parent-reported infant gastro-oesophageal reflux: A population-based study. J Paediatr Child Health. 2014(Nov 11):[Epub ahead of print].


Hussain M, Batool F, Masood-Us-Syed SS. Association of various factors with infantile colic. Pak Paed J. 2013;37(4):217-21.

Ineligible outcomes

Hussain S, Kierkus J, Hu P, Hoffman D, Lekich R, Sloan S, et al. Safety and efficacy of delayed release rabeprazole in 1- to 11-month-old infants with symptomatic GERD. J Pediatr Gastroenterol Nutr. 2014;58(2):226-36.



reflux)

Iacono G, Merolla R, D'Amico D, Bonci E, Cavataio F, Di Prima L, et al. Gastrointestinal symptoms in infancy: a population-based prospective study. Dig Liver Dis. 2005;37(6):432-8.

Prevalence study

Iacovou M, Ralston RA, Muir J, Walker KZ, Truby H. Dietary management of infantile colic: a systematic review. Matern Child Health J. 2012;16(6):1319-31.

Literature review

Indrio F, Di Mauro A, Riezzo G, Cavallo L, Francavilla R. Infantile colic, regurgitation, and constipation: an early traumatic insult in the development of functional gastrointestinal disorders in children? Eur J Pediatr. 2015;174(6):841-2.


Indrio F, Di Mauro A, Riezzo G, Civardi E, Intini C, Corvaglia L, et al. Prophylactic use of a probiotic in the prevention of colic, regurgitation, and functional constipation: a randomized clinical trial. JAMA Pediatr. 2014;168(3):228-33.



reflux)

Indrio F, Di Mauro A, Riezzo G, Panza R, Cavallo L, Francavilla R. Prevention of functional gastrointestinal disorders in neonates: Clinical and socioeconomic impact. Benef Microbes. 2015;6(2):195-98.

Literature review

Indrio F, Riezzo G, Raimondi F, Bisceglia M, Cavallo L, Francavilla R. The effects of probiotics on feeding tolerance, bowel habits, and gastrointestinal motility in preterm newborns. J Pediatr. 2008;152(6):801-6.


Indrio F, Riezzo G, Raimondi F, Cavallo L, Francavilla R. Regurgitation in healthy and non healthy infants. Ital J Pediatr. 2009;35(1):39.

Literature review

Indrio F. Randomised controlled trial: Study concludes L. reuteri not effective for infant colic, but findings may be limited by participants' heterogeneity. Evid Based Med. 2014;19(6):215.


Jadcherla SR, Slaughter JL, Stenger MR, Klebanoff M, Kelleher K, Gardner W. Practice Variance, Prevalence, and Economic Burden of Premature Infants Diagnosed With GERD. Hosp Pediatr. 2013;3(4):335-41.


Johnson JD, Cocker K, Chang E. Infantile Colic: Recognition and Treatment. Am Fam Physician. 2015;92(7):577-82.

Literature review

Jordan B, Heine RG, Meehan M, Catto-Smith AG, Lubitz L. Effect of antireflux medication, placebo and infant mental health intervention on persistent crying: a randomized clinical trial. J Paediatr Child Health. 2006;42(1-2):49-58.



reflux)

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Jordan GJ. Elimination communication as colic therapy. Med Hypotheses. 2014;83(3):282-5.


Khan ZA, Ahmad S, Sheikh MY. Gastro esophageal reflux: an over investigated entity in neonates and infants. JPMA J Pak Med Assoc. 2010;60(12):984-6.



reflux)

Khoshoo V, Dhume P. Clinical response to 2 dosing regimens of lansoprazole in infants with gastroesophageal reflux. J Pediatr Gastroenterol Nutr. 2008;46(3):352-4.



reflux)

Kirby CN, Segal AY, Hinds R, Jones KM, Piterman L. Infant gastro-oesophageal reflux disease (GORD): Australian GP attitudes and practices. J Paediatr Child Health. 2016;52(1):47-53.


Koivusalo AI, Pakarinen MP, Wikstrom A, Rintala RJ. Assessment and treatment of gastroesophageal reflux in healthy infants with apneic episodes: a retrospective analysis of 87 consecutive patients. Clin Pediatr. 2011;50(12):1096-102.



reflux)

Kokke FT, Scholtens PA, Alles MS, Decates TS, Fiselier TJ, Tolboom JJ, et al. A dietary fiber mixture versus lactulose in the treatment of childhood constipation: a double-blind randomized controlled trial. J Pediatr Gastroenterol Nutr. 2008;47(5):592-7.


Koppen IJN, Lammers LA, Benninga MA, Tabbers MM. Management of Functional Constipation in Children: Therapy in Practice. Paediatr Drugs. 2015;17(5):349-60.


Korterink JJ, Ockeloen L, Benninga MA, Tabbers MM, Hilbink M, Deckers-Kocken JM. Probiotics for childhood functional gastrointestinal disorders: a systematic review and meta-analysis. Acta Paediatr. 2014;103(4):365-72.

Literature review

Kramer EA, den Hertog-Kuijl JH, van den Broek LM, van Leengoed E, Bulk AM, Kneepkens CM, et al. Defecation patterns in infants: a prospective cohort study. Arch Dis Child. 2015;100(6):533-6.

Ineligible study design: prevalence

study

Kuizenga-Wessel S, Benninga MA, Tabbers MM. Reporting outcome measures of functional constipation in children from 0 to 4 years of age. J Pediatr Gastroenterol Nutr. 2015;60(4):446-56.

Literature review

Kurowski J, Kaur S, Katsogridakis Y, Wershil BK, Bass LM. Educational Module Improves Emergency Department Evaluation for Suspected Constipation. J Pediatr. 2015;167(3):706-10.e1.


Landgren K, Hallstrom I. Parents' experience of living with a baby with infantile colic--a phenomenological hermeneutic study. Scand J Caring Sci. 2011;25(2):317-24.

Ineligible outcomes

Landgren K. Acupuncture in Practice: Investigating Acupuncturists' Approach to Treating Infantile Colic. Evid Based Complement Alternat Med. 2013. :Article ID 456712.

Ineligible outcomes

Landgren K, Tiberg I, Hallstrom I. Standardized minimal acupuncture, individualized acupuncture, and no acupuncture for infantile colic: study protocol for a multicenter randomized controlled trial - ACU-COL. BMC Altern Med. 2015;15:325.


Levitt MA, Pena A. Minimally invasive treatment of fecal incontinence and constipation in children. Minerva Chir. 2010;65(2):223-34.


Liem O, Harman J, Benninga M, Kelleher K, Mousa H, Di Lorenzo C. Health utilization and cost impact of childhood constipation in the United States. J Pediatr. 2009;154(2):258-62.


Litmanovitz I, Bar-Yoseph F, Lifshitz Y, Davidson K, Eliakim A, Regev RH, et al. Reduced crying in term infants fed high beta-palmitate formula: a double-blind randomized clinical trial. BMC Pediatr. 2014;14:152.


Loening-Baucke V, Pashankar DS. A randomized, prospective, comparison study of polyethylene glycol 3350 without electrolytes and milk of magnesia for children with constipation and fecal incontinence. Pediatrics. 2006;118(2):528-35.


Loots C, Kritas S, van Wijk M, McCall L, Peeters L, Lewindon P, et al. Body Ineligible

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positioning and medical therapy for infantile gastroesophageal reflux symptoms. J Pediatr Gastroenterol Nutr. 2014;59(2):237-43.

population (babies with

gastroesophageal reflux)

Martigne L, Delaage PH, Thomas-Delecourt F, Bonnelye G, Barthelemy P, Gottrand F. Prevalence and management of gastroesophageal reflux disease in children and adolescents: a nationwide cross-sectional observational study. Eur J Pediatr. 2012;171(12):1767-73.


Maxted AE, Dickstein S, Miller-Loncar C, High P, Spritz B, Liu J, et al. Infant colic and maternal depression. Infant Ment Health J. 2005;26(1):56-68.

Ineligible outcomes

Miller J. Cry babies: A framework for chiropractic care. Clin Chiropr. 2007;10(3):139-46.


Miller J, Caprini Croci S. Cry baby, why baby? Beyond colic: Is it time to widen our views? J Clin Chiropr Pediatr. 2005;6:419-23.

Literature review

Miller JE. Costs of Routine Care for Infant Colic in the UK and Costs of Chiropractic Manual Therapy as a Management Strategy Alongside a RCT for this Condition. J Clin Chiropr Pediatr. 2013;14(1):1063-69.


Miyazawa R, Tomomasa T, Kaneko H, Arakawa H, Morikawa A. Effect of formula thickened with reduced concentration of locust bean gum on gastroesophageal reflux. Acta Paediatr. 2007;96(6):910-4.



reflux)

Mugie SM, Di Lorenzo C, Benninga MA. Constipation in childhood. Nat Rev Gastroenterol Hepatol. 2011;8(9):502-11.

Literature review

Mugie SM, Korczowski B, Bodi P, Green A, Kerstens R, Ausma J, et al. Prucalopride is no more effective than placebo for children with functional constipation. Gastroenterology. 2014;147(6):1285-95.e1.


Nel ED. Gastro-oesophageal reflux in infants and children. S Afr Fam Pract. 2013;54(5):414-17.

Literature review

Neu M, Schmiege SJ, Pan Z, Fehringer K, Workman R, Marcheggianni-Howard C, et al. Interactions during feeding with mothers and their infants with symptoms of gastroesophageal reflux. J Altern Complement Med. 2014;20(6):493-9.

Ineligible outcomes

Ngoenmak T, Treepongkaruna S, Buddharaksa Y, Khositseth A. Effects of Domperidone on QT Interval in Children with Gastroesophageal Reflux Disease. Pediatr neonatol. 2016;57(1):60-4.



reflux)

Noviello C, Romano M, Zangari A, Papparella A, Martino A, Cobellis G. Management of severe constipation in children. Minerva Pediatr. 2013;65(2):193-8.


Omari T, Davidson G, Bondarov P, Naucler E, Nilsson C, Lundborg P. Pharmacokinetics and acid-suppressive effects of esomeprazole in infants 1-24 months old with symptoms of gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr. 2007;45(5):530-7.



reflux)

Omari TI, Benninga MA, Sansom L, Butler RN, Dent J, Davidson GP. Effect of baclofen on esophagogastric motility and gastroesophageal reflux in children with gastroesophageal reflux disease: A randomized controlled trial. J Pediatr. 2006;149(4):468-74.e2.


Osatakul S, Puetpaiboon A. Use of Rome II versus Rome III criteria for diagnosis of functional constipation in young children. Pediatr Int. 2014;56(1):83-8.

Prevalence study

Ostrom KM, Jacobs JR, Merritt RJ, Murray RD. Decreased regurgitation with a soy formula containing added soy fiber. Clin Pediatr (Phila). 2006;45(1):29-36.



reflux)

Papadopoulou F, Tsampoulas C, Siomou E, Tzovara J, Siamopoulou A, Efremidis SC. Cyclic contrast-enhanced harmonic voiding urosonography for the evaluation of reflux. Can we keep the cost of the examination low? Eur Radiol. 2006;16(11):2521-6.


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Phatak UP, Pashankar DS. Role of polyethylene glycol in childhood constipation. Clin Pediatr. 2014;53(10):927-32.


Quitadamo P, Miele E, Alongi A, Brunese FP, Di Cosimo ME, Ferrara D, et al. Italian survey on general pediatricians' approach to children with gastroesophageal reflux symptoms. Eur J Pediatr. 2015;174(1):91-6.



reflux)

Rafati MR, Karami H, Salehifar E, Karimzadeh A. Clinical efficacy and safety of polyethylene glycol 3350 versus liquid paraffin in the treatment of pediatric functional constipation. DARU J Pharma Sci. 2011;19(2):154-58.


Ratanamongkol P, Lertmaharit S, Jongpiputvanich S. Polyethylene glycol 4000 without electrolytes versus milk of magnesia for the treatment of Functional constipation in infants and young children: A randomized controlled trial. Asian Biomed. 2009;3(4):391-99.


Reinthal M, Lund I, Lundeberg T. Acupuncture in baby colic. Accu Rel Ther. 2013;1(2-3):31-34.


Rodriguez LA, Flores A, Doody DP. Evaluation and Management of Intractable Constipation in Children. Semin Colon Rectal Surg. 2006;17(1):29-37.

Literature review

Rouster AS, Karpinski AC, Silver D, Monagas J, Hyman PE. Functional Gastrointestinal Disorders Dominate Pediatric Gastroenterology Outpatient Practice. J Pediatr Gastroenterol Nutr. 2016;62(6):847-51.

Prevalence study

Sacco O, Mattioli G, Girosi D, Battistini E, Jasonni V, Rossi GA. Gastroesophageal reflux and its clinical manifestation at gastroenteric and respiratory levels in childhood: physiology, signs and symptoms, diagnosis and treatment. Expert Rev Respir Med. 2007;1(3):391-401.

Literature review

Salvatore S, Hauser B, Salvatoni A, Vandenplas Y. Oral ranitidine and duration of gastric pH >4.0 in infants with persisting reflux symptoms. Acta Paediatr. 2006;95(2):176-81.



reflux)

Saps M, Youssef N, Miranda A, Nurko S, Hyman P, Cocjin J, et al. Multicenter, randomized, placebo-controlled trial of amitriptyline in children with functional gastrointestinal disorders. Gastroenterology. 2009;137(4):1261-9.


Semeniuk J, Kaczmarski M. Gastroesophageal reflux in children and adolescents. clinical aspects with special respect to food hypersensitivity. Adv Med Sci. 2006;51:327-35.


Shanmuganathan S. Compliance by Australasian Paediatricians with the 2009 Naspghan-Espghan Guideline for the Diagnosis and Management of Gastro-Oesophageal Reflux in Children. Gastro Open Access. 2015;3(119):1-8.


Steutel NF, Benninga MA, Langendam MW, de Kruijff I, Tabbers MM. Reporting outcome measures in trials of infant colic. J Pediatr Gastroenterol Nutr. 2014;59(3):341-6.

Literature review

Sullivan JS, Sundaram SS. Gastroesophageal reflux. Pediatr Rev. 2012;33(6):243-53.

Literature review

Sung V, Hiscock H, Tang M, Mensah FK, Heine RG, Stock A, et al. Probiotics to improve outcomes of colic in the community: protocol for the Baby Biotics randomised controlled trial. BMC Pediatr. 2012;12:135.


Suskind DL, Thompson DM, Gulati M, Huddleston P, Liu DC, Baroody FM. Improved infant swallowing after gastroesophageal reflux disease treatment: a function of improved laryngeal sensation? Laryngoscope. 2006;116(8):1397-403.



reflux)

Tappin D, Nawaz S, McKay C, MacLaren L, Griffiths P, Mohammed TA. Development of an early nurse led intervention to treat children referred to secondary paediatric care with constipation with or without soiling. BMC Pediatr. 2013;13:193.


Terblanche A. Gastro-oesphageal reflux disease in infants. S Afr Pharm J. 2010;78(7):24-26.

Literature review

Turco R, Miele E, Russo M, Mastroianni R, Lavorgna A, Paludetto R, et al. Early-life factors associated with pediatric functional constipation. J Pediatr Gastroenterol Nutr. 2014;58(3):307-12.

Prevalence study

Ummarino D, Miele E, Martinelli M, Scarpato E, Crocetto F, Sciorio E, et al. Ineligible patient

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Effect of magnesium alginate plus simethicone on gastroesophageal reflux in infants. J Pediatr Gastroenterol Nutr. 2015;60(2):230-5.

population

Urganci N, Akyildiz B, Polat TB. A comparative study: the efficacy of liquid paraffin and lactulose in management of chronic functional constipation. Pediatr Int. 2005;47(1):15-9.


Ustundag G, Kuloglu Z, Kirbas N, Kansu A. Can partially hydrolyzed guar gum be an alternative to lactulose in treatment of childhood constipation? Turk J Gastroenterol. 2010;21(4):360-4.


Utokpat P, Chongsrisawat V. Management of functional gastrointestinal disorders in infants: A survey of pediatricians' perspective [Conference Abstract]. Neurogastroenterol Motil. 2014;26:78.

Conference abstract

van Sleuwen BE, L'Hoir MP, Engelberts AC, Busschers WB, Westers P, Blom MA, et al. Comparison of behavior modification with and without swaddling as interventions for excessive crying. J Pediatr. 2006;149(4):512-7.

Ineligible outcomes

van Tilburg MAL, Hyman PE, Walker L, Rouster A, Palsson OS, Kim SM, et al. Prevalence of functional gastrointestinal disorders in infants and toddlers. J Pediatr. 2015;166(3):684-9.


van Wering HM, Tabbers MM, Benninga MA. Are constipation drugs effective and safe to be used in children? A review of the literature. Expert Opin Drug Saf. 2012;11(1):71-82.

Literature review

Varni JW, Bendo CB, Nurko S, Shulman RJ, Self MM, Franciosi JP, et al. Health-related quality of life in pediatric patients with functional and organic gastrointestinal diseases. J Pediatr. 2015;166(1):85-90.


Vivatvakin B, Mahayosnond A, Theamboonlers A, Steenhout PG, Conus NJ. Effect of a whey-predominant starter formula containing LCPUFAs and oligosaccharides (FOS/GOS) on gastrointestinal comfort in infants. Asia Pac J Clin Nutr. 2010;19(4):473-80.


Vlieger AM, Blink M, Tromp E, Benninga MA. Use of complementary and alternative medicine by pediatric patients with functional and organic gastrointestinal diseases: Results from a multicenter survey. Pediatrics. 2008;122(2):e446-e51.


Vlieger AM, Benninga MA. Complementary therapies for pediatric functional gastrointestinal disorders. J Pediatr Gastroenterol Nutr. 2008;47(5):707-09.


Xinias I, Mouane N, Le Luyer B, Spiroglou K, Demertzidou V, Hauser B, et al. Cornstarch thickened formula reduces oesophageal acid exposure time in infants. Dig Liver Dis. 2005;37(1):23-7.



reflux)

Xu M, Wang J, Wang N, Sun F, Wang L, Liu XH. The Efficacy and Safety of the Probiotic Bacterium Lactobacillus reuteri DSM 17938 for Infantile Colic: A Meta-Analysis of Randomized Controlled Trials. PLOS ONE. 2015;10(10):e0141445.

Literature review

Yang CH, Punati J. Practice patterns of pediatricians and trainees for the management of functional constipation compared with 2006 NASPGHAN guidelines. J Pediatr Gastroenterol Nutr. 2015;60(3):308-11.


Yang M, Chen P-Y, Gong S-T, Lyman B, Geng L-L, Liu L-Y, et al. Cost-effectiveness analysis of an enteral nutrition protocol for children with common gastrointestinal diseases in China: good start but still a long way to go. JPEN J Parenter Enteral Nutr. 2014;38(2 Suppl):72S-6S.


Young RJ, Beerman LE, Vanderhoof JA. Increasing oral fluids in chronic constipation in children. Gastroenterol Nurs. 1998;21(4):156-61.

Pre 2005 study

Zohalinezhad ME, Imanieh MH, Samani SM, Mohagheghzadeh A, Dehghani SM, Haghighat M, et al. Effects of Quince syrup on clinical symptoms of children with symptomatic gastroesophageal reflux disease: A double-blind randomized controlled clinical trial. Complement Ther Clin Pract. 2015;21(4):268-76.


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1

Two documents report the methods and results for this review:

The systematic review protocol is published in Glanville J, et al. BMJ Open 2016;6:e011475. doi:10.1136/bmjopen-2016-011475

The results of the systematic review are provided in the supplementary file

Section/topic # Checklist item Document: page/section

TITLE

Title 1 Identify the report as a systematic review, meta-analysis, or both. Supplementary file: Section 1

ABSTRACT

Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.

BMJ Open Protocol: Pg.1

INTRODUCTION

Rationale 3 Describe the rationale for the review in the context of what is already known. BMJ Open Protocol*: Pg.1-2

Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

BMJ Open Protocol*: Pg.2-4

METHODS

Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.

BMJ Open Protocol*: Pg.2

Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and Supplementary file characteristics (e.g.,

years considered, language, publication status) used as criteria for eligibility, giving rationale.

BMJ Open Protocol*: Pg.2-4 and Table 1

Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

Supplementary file: Section 1 BMJ Open Protocol*: Pg.4-6

Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

Supplementary file: Appendix A

BMJ Open Protocol*: Figure 3

Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if

applicable, included in the meta-analysis).

BMJ Open Protocol*: Pg.6-7

Data collection process 10 Describe method of data extraction from Supplementary files (e.g., piloted forms, independently, in duplicate) BMJ Open Protocol*:

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2

and any processes for obtaining and confirming data from investigators. Pg.6

Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

BMJ Open Protocol*: Pg.6 and Table 2

Risk of bias in individual studies

12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.


Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). BMJ Open Protocol*: Pg.3

Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of

consistency (e.g., I2) for each meta-analysis.

BMJ Open Protocol*: Pg.6 -7

Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective Supplementary filing within studies).


Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done,

indicating which were pre-specified.


RESULTS

Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

Supplementary file: Sections 1.1 and 1.2. Figure 1.1, Table 1.2, Appendix B.

Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.

Supplementary file: Tables 1.2, 1.3, 1.4 and 1.5.

Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). Supplementary file: Section 1.5, Tables 1.6, 1.7 and 1.8

Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

Supplementary file: Section 1.4

Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. No meta-analyses were possible.

Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). Supplementary file: Section 1.5, Tables 1.6, 1.7 and 1.8

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Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]).

The cost of illness calculation is presented in this paper.

DISCUSSION

Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

Supplementary file: Sections 1.4 and 1.6

Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, Supplementary fileing bias).


Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.


FUNDING

Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.

BMJ Open Protocol*: Pg.7.

This review was funded by Nutricia Research.

*Glanville J, Ludwig T, Lifschitz C et al. (2016) Costs associated with functional gastrointestinal disorders and related signs and symptoms in infants: a systematic review protocol. BMJ Open 6, e011475.

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Supplementary fileing Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7):

e1000097. doi:10.1371/journal.pmed1000097. For more information, visit: www.prisma-statement.org.

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